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Inside and out: the activities of senescence in cancer

Nature Reviews Cancer volume 14, pages 547–558 (2014)Cite this article

Subjects

Key Points

  • Induction of senescence, a stable state of cell cycle arrest, was originally described in normal cells, but it can also be induced in tumour cells in response to various stresses.

  • Senescent cells are metabolically active. In contrast to tumour cells, which typically preferentially use glycolysis in the presence of oxygen to generate energy, senescent cells can exhibit hyperactive mitochondrial respiration (oxidative phosphorylation) in some contexts.

  • Autophagy is activated during senescence, but its importance varies depending on the context.

  • The senescence-associated secretory phenotype (SASP) mediates the diverse functionality of senescent cells in an autocrine and paracrine manner, including reinforcing or inducing senescence, activating an immune response and even promoting tumorigenesis, depending on the context.

  • Senescent cells can be eliminated through a SASP-induced immune response, which can involve both innate and adaptive immunity.

  • Various triggers, such as tissue damage or tumorigenesis-associated stresses, can cause stromal cell senescence, which may either facilitate or inhibit tumour progression, depending on the context.

Abstract

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.

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Figure 1: Glucose metabolism in oncogene-induced senescence (OIS) and therapy-induced senescence (TIS).
Figure 2: The senescence-associated secretory phenotype (SASP) and its implication for the tumour microenvironment.
Figure 3: Senescence in the stroma of the liver.

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References

  1. Campisi, J. & D'adda Di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell. Biol. 8, 729–740 (2007).

    Article  CAS  Google Scholar 

  2. D'adda Di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer 8, 512–522 (2008).

    Article  CAS  Google Scholar 

  3. Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Hoare, M. & Narita, M. Transmitting senescence to the cell neighbourhood. Nature Cell Biol. 15, 887–889 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  PubMed  Google Scholar 

  8. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  PubMed  Google Scholar 

  9. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. D'adda Di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Herbig, U., Jobling, W. A., Chen, B. P. C., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, 53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Blasco, M. A. Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging. EMBO J. 24, 1095–1103 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. González-Suárez, E., Samper, E., Flores, J. M. & Blasco, M. A. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nature Genet. 26, 114–117 (2000).

    Article  PubMed  Google Scholar 

  14. Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97, 515–525 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Qi, L. et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. 63, 8188–8196 (2003).

    CAS  PubMed  Google Scholar 

  16. Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Feldser, D. M. & Greider, C. W. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11, 461–469 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). This seminal paper established the concept of OIS.

    Article  CAS  PubMed  Google Scholar 

  20. Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 12, 2997–3007 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Collado, M. et al. Tumour biology: Senescence in premalignant tumours. Nature 436, 642–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). This is a seminal study that identified OIS of human melanocytic naevi.

    Article  CAS  PubMed  Google Scholar 

  26. Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol. 25, 2660–2672 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. Shamma, A. et al. Rb regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell 15, 255–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Courtois-Cox, S. et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10, 459–472 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gewinner, C. et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16, 115–125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chang, B. D. et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59, 3761–3767 (1999).

    CAS  PubMed  Google Scholar 

  31. Poele te, R. H., Okorokov, A. L., Jardine, L., Cummings, J. & Joel, S. P. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62, 1876–1883 (2002).

    Google Scholar 

  32. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). This was the first study showing that chemotherapy-induced tumour senescence contributed to improved survival in mice, in an apoptosis defective context.

    Article  CAS  PubMed  Google Scholar 

  33. Wu, C.-H. et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc. Natl Acad. Sci. USA 104, 13028–13033 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). This was the first study to show that the innate immune response eliminates the senescent cells induced in tumours in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Reimann, M. et al. Tumor stroma-derived TGF-b limits Myc-Driven lymphomagenesisvia Suv39h1-dependent senescence. Cancer Cell 17, 262–272 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Ewald, J. A., Desotelle, J. A., Wilding, G. & Jarrard, D. F. Therapy-induced senescence in cancer. J. Natl Cancer Inst. 102, 1536–1546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nardella, C., Clohessy, J. G., Alimonti, A. & Pandolfi, P. P. Pro-senescence therapy for cancer treatment. Nature Rev. Cancer 11, 503–511 (2011).

    Article  CAS  Google Scholar 

  39. Acosta, J. C. & Gil, J. Senescence: a new weapon for cancertherapy. Trends Cell Biol. 22, 211–219 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011).

    Article  CAS  Google Scholar 

  41. Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013). This study established the metabolic profile of OIS cells, identifying active PDH with increased mitochondrial respiration during OIS.

    Article  CAS  PubMed  Google Scholar 

  42. Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005).

    CAS  PubMed  Google Scholar 

  43. Dörr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013). This study shows that in a TIS model, the SASP, which provokes endoplasmic reticulum stress, is associated with increased glucose use, hyperactive mitochondrial respiration, and autophagy activation, and that TIS cells are sensitive to blocking glucose use or autophagy, which causes endoplasmic reticulum-related apoptosis.

    Article  PubMed  CAS  Google Scholar 

  44. Poulikakos, P. I. & Rosen, N. Mutant BRAF melanomas—dependence and resistance. Cancer Cell 19, 11–15 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Michelakis, E. D., Webster, L. & Mackey, J. R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989–994 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vazquez, F. et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. St-Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Jiang, P., Du, W., Mancuso, A., Wellen, K. E. & Yang, X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693 (2013). This study shows that malic enzymes and p53 reciprocally repress each other and that depletion of ME1 or ME2 induces senescence in both normal and tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baggetto, L. G. Deviant energetic metabolism of glycolytic cancer cells. Biochimie 74, 959–974 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Ren, J.-G., Seth, P., Everett, P., Clish, C. B. & Sukhatme, V. P. Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS ONE 5, e12520 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Quijano, C. et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11, 1383–1392 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Passos, J. F., Saretzki, G. & Zglinicki Von, T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 35, 7505–7513 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Passos, J. F. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. Plos Biol. 5, e110 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Moiseeva, O. et al. Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol. Cell. Biol. 29, 4495–4507 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Young, A. R. J. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009). This study shows that autophagy is activated during senescence and that the inhibition of autophagy delays the onset of senescence and the SASP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nature 13, 453–460 (2011).

    CAS  Google Scholar 

  61. Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang, Y. et al. Autophagic activity dictates the cellular response to oncogenic RAS. Proc. Natl Acad. Sci. 109, 13325–13330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tuveson, D. A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Hoare, M., Young, A. R. J. & Narita, M. Autophagy in cancer: Having your cake and eating it. Semin. Cancer Biol. 21, 397–404 (2011).

    CAS  PubMed  Google Scholar 

  66. Yang, Z. J., Chee, C. E., Huang, S. & Sinicrope, F. A. The role of autophagy in cancer: therapeutic implications. Mol. Cancer Ther. 10, 1533–1541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gewirtz, D. A. Autophagy and senescence in cancer therapy. J. Cell. Physiol. 229, 6–9 (2014).

    CAS  PubMed  Google Scholar 

  68. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mariño, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573–18583 (2007).

    Article  PubMed  Google Scholar 

  72. Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gewirtz, D. A. Autophagy and senescence: a partnership in search of definition. Autophagy 9, 808–812 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, B. Y. et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell 5, 187–195 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Gerland, L.-M. et al. Association of increased autophagic inclusions labeled for β-galactosidase with fibroblastic aging. Exp. Gerontol. 38, 887–895 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Leidal, A. M., Cyr, D. P., Hill, R. J., Lee, P. W. K. & McCormick, C. Subversion of autophagy by Kaposi's sarcoma-associated herpesvirus impairs oncogene-induced senescence. Cell Host Microbe 11, 167–180 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Mosieniak, G. et al. Curcumin induces permanent growth arrest of human colon cancer cells: link between senescence and autophagy. Mech. Ageing Dev. 133, 444–455 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Goehe, R. W. et al. The autophagy-senescence connection in chemotherapy: must tumor cells (self) eat before they sleep? J. Pharmacol. Exp. Ther. 343, 763–778 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Knizhnik, A. V. et al. Survival and death strategies in glioma cells: autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damage. PLoS ONE 8, e55665 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Patel, K. R. et al. Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci. Transl. Med. 5, 205ra133 (2013).

    Article  PubMed  CAS  Google Scholar 

  81. Qi, M. et al. Pseudolaric acid B-induced autophagy contributes to senescence via enhancement of ROS generation and mitochondrial dysfunction in murine fibrosarcoma L929 cells. J. Pharmacol. Sci. 121, 200–211 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Qi, M. et al. mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in Psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells. Eur. J. Pharmacol. 715, 76–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Patschan, S. et al. Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 294, H1119–H1129 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Kang, H. T., Lee, K. B., Kim, S. Y., Choi, H. R. & Park, S. C. Autophagy impairment induces premature senescence in primary human fibroblasts. PLoS ONE 6, e23367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Janku, F., McConkey, D. J., Hong, D. S. & Kurzrock, R. Autophagy as a target for anticancer therapy. Nature Rev. Clin. Oncol. 8, 528–539 (2011).

    Article  CAS  Google Scholar 

  86. Amaravadi, R. K. et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17, 654–666 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2014).

    Article  CAS  Google Scholar 

  88. Guo, J. Y. et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 27, 1447–1461 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nature Rev. Cancer 9, 81–94 (2009).

    Article  CAS  Google Scholar 

  90. Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). References 91 and 92 describe the crucial role of pro-inflammatory cytokines and their receptors in senescence.

    Article  CAS  PubMed  Google Scholar 

  93. Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biol. 15, 978–990 (2013). This study identified the inflammasome as a critical regulator of the SASP.

    Article  CAS  PubMed  Google Scholar 

  94. Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature 11, 973–979 (2009).

    CAS  Google Scholar 

  97. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). This is an interesting study that shows a functional connection between obesity-induced senescence and a stromal SASP.

    Article  CAS  PubMed  Google Scholar 

  98. Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. & Campisi, J. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Davalos, A. R. et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Millis, A. J., Hoyle, M., McCue, H. M. & Martini, H. Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. Exp. Cell Res. 201, 373–379 (1992).

    Article  CAS  PubMed  Google Scholar 

  101. Goldstein, S., Moerman, E. J., Fujii, S. & Sobel, B. E. Overexpression of plasminogen activator inhibitor type-1 in senescent fibroblasts from normal subjects and those with Werner syndrome. J. Cell. Physiol. 161, 571–579 (1994).

    Article  CAS  PubMed  Google Scholar 

  102. Kortlever, R. M., Higgins, P. J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nature Cell Biol. 8, 877–884 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Parrinello, S., Coppé, J.-P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118, 485–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. Plos Biol. 6, 2853–2868 (2008).

    Article  PubMed  CAS  Google Scholar 

  106. Hubackova, S. et al. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging 4, 932–951 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Scurr, L. L. et al. IGFBP7 is not required for B-RAF-induced melanocyte senescence. Cell 141, 717–727 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Role for IGFBP7 in senescence induction by BRAF. Cell 141, 746–747 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jackson, J. G. et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21, 793–806 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hoenicke, L. & Zender, L. Immune surveillance of senescent cells—biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Kang, T.-W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This is a seminal study that identifies senescence surveillance involving the adaptive immune response.

    Article  CAS  PubMed  Google Scholar 

  113. Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013). This study suggests that NK cells that are recruited to the tumour lesion by the SASP of senescent tumour cells may also kill non-senescent tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rakhra, K. et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18, 485–498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This was the first study to show that HSC senescence controls fibrosis through the SASP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Kim, K.-H., Chen, C.-C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jun, J.-I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biol. 12, 676–685 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152, 340–351 (2013). This study shows a close and general correlation between stromal senescence and early neoplastic events in a new p16-'monitor' mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Braumüller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013). This study shows that tumours can be induced into senescence by cytokines that are derived from TAA-activated CD4+ T H 1 cells.

    Article  PubMed  CAS  Google Scholar 

  127. Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. & Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Müller-Hermelink, N. et al. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507–518 (2008).

    Article  PubMed  CAS  Google Scholar 

  129. Casanovas, O., Hager, J. H., Chun, M. G. H. & Hanahan, D. Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene 24, 6597–6604 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Quesnel, B. Tumor dormancy and immunoescape. APMIS 116, 685–694 (2008).

    Article  PubMed  Google Scholar 

  131. Lengagne, R. et al. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J. Immunol. 180, 130–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nature Rev. Cancer 13, 759–771 (2013).

    Article  CAS  Google Scholar 

  134. Nickoloff, B. J., Ben-Neriah, Y. & Pikarsky, E. Inflammation and cancer: is the link as simple as we think? J. Invest. Dermatol. 124, x–xiv (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Nickoloff, B. J. Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. J. Cutan. Pathol. 28, 57–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Nickoloff, B. J. & Nestle, F. O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J. Clin. Invest. 113, 1664–1675 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kaelin, W. G. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell. Metab. 16, 9–17 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Draoui, N. & Feron, O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis. Model. Mech. 4, 727–732 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Dickins, R. A. et al. Tissue-specific and reversible RNA interference in transgenic mice. Nature Genet. 39, 914–921 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Pribluda, A. et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Cristofalo, V. J., Lorenzini, A., Allen, R. G., Torres, C. & Tresini, M. Replicative senescence: a critical review. Mech. Ageing Dev. 125, 827–848 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Sharpless, N. E. & Depinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007).

    Article  CAS  Google Scholar 

  146. Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature 10, 825–836 (2008).

    CAS  Google Scholar 

  147. Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).

    Article  CAS  PubMed  Google Scholar 

  148. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2012).

    Article  CAS  Google Scholar 

  149. Muñoz-Espín, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    Article  PubMed  CAS  Google Scholar 

  150. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Schlomm, T. et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod. Pathol. 21, 1371–1378 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell. Biol. 13, 283–296 (2012).

    Article  CAS  Google Scholar 

  155. Soucek, L. et al. Modelling Myc inhibition as a cancer therapy. Nature 455, 679–683 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lin, H.-K. et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464, 374–379 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Campaner, S. et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nature 12, 54–59 (2010).

    CAS  Google Scholar 

  158. Puyol, M. et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Chan, C.-H. et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 154, 556–568 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Wall, M. et al. The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 3, 82–95 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank C. Frezza and D. T. Fearon for their thoughtful discussions, as well as M. Hoare, Masako Narita and other members of Narita group, for critical reading and discussions. This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa and the Human Frontier Science Program (M.N.).

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Authors and Affiliations

  1. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

    Pedro A. Pérez-Mancera, Andrew R. J. Young & Masashi Narita

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  1. Pedro A. Pérez-Mancera
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  2. Andrew R. J. Young
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  3. Masashi Narita
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Correspondence to Masashi Narita.

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Glossary

Warburg effect

A shift in glucose metabolism from mitochondrial oxidative phosphorylation to glycolysis in the presence of ample oxygen.

NADPH

The reduced form of NADP+ and a source of reducing equivalents. Major sources of NADPH include the pentose phosphate pathway, NADP-dependent malic enzymes and NADP-dependent isocitrate dehydrogenase.

Pancreatic intraepithelial neoplasias

(PanINs). Neoplasias that are usually induced by activating mutations in KRAS and represent the most common precursor lesion of pancreatic ductal adenocarcinoma.

Cytokines

A broad class of small proteins that comprise chemokines, interferons, interleukins, lymphokines and tumour necrosis factors that are produced by various cells.

Inflammasomes

Cytosolic multiprotein innate immune complexes that assemble in response to various stimuli and that activate the pro-inflammatory serine protease caspase 1. Inflammasomes initiate innate immune responses by cleaving the inflammatory cytokines pro-interleukin-1 ß (pro-IL-1ß) and pro-IL-18, leading to their activation and secretion.

Macrophages

Generally, M1-polarized macrophages inhibit cell proliferation and cause tissue damage, whereas M2-polarized macrophages promote cell proliferation and tissue repair. The M1 and M2 macrophages promote the T helper 1 (TH1) and TH2 cell responses, respectively.

Natural killer cells

(NK cells). A subgroup of white blood cells that is implicated in the killing of tumour or virus-infected cells. They are generally considered to be the cytotoxic lymphocytes of innate immunity owing to their lack of antigen-specific cell surface receptors, but they can also exert antibody-dependent cell cytotoxicity.

TH1 cell

T helper 1 (TH1) cells are a subset of CD4+ T helper cells that secrete cytokines, including interferon-γ (IFNγ) and tumour necrosis factor (TNF). They are canonically associated with the stimulation of CD8+ cytotoxic T lymphocytes and macrophages, as well as antitumour immunity.

Enterohepatic circulation

The circulation between the liver and the intestine. Bile acids and other substances excreted from the liver are reabsorbed by the enterocytes into the hepatic portal vein.

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Pérez-Mancera, P., Young, A. & Narita, M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer 14, 547–558 (2014). https://doi.org/10.1038/nrc3773

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