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The power and the promise of oncogene-induced senescence markers

Abstract

Recently, it has been shown that oncogene-induced senescence (OIS) occurs during the early stages of tumorigenesis. Senescent tumour cells are abundant within premalignant neoplastic lesions, whereas they are scarce in malignant tumours. This association of senescence with the premalignant stages of tumour progression opens the possibility of using senescence markers as diagnostic and prognostic tools. Moreover, some chemotherapeutic protocols induce senescence in tumour cells and, consequently, senescence markers could help to monitor treatment response.

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Figure 1: Many roads to senescence.
Figure 2: Senescence in premalignant neoplastic lesions.
Figure 3: Senescence index.

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References

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

    Article  CAS  Google Scholar 

  2. Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001).

    Article  CAS  Google Scholar 

  3. Shay, J. W. & Roninson, I. B. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23, 2919–2933 (2004).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    Article  CAS  Google Scholar 

  9. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    Article  CAS  Google Scholar 

  10. Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).

    Article  CAS  Google Scholar 

  11. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    Article  CAS  Google Scholar 

  12. Lo, T. L. et al. Sprouty and cancer: the first terms report. Cancer Lett. 6 Feb 2006 [epub ahead of print].

  13. Furukawa, T., Sunamura, M., Motoi, F., Matsuno, S. & Horii, A. Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am. J. Pathol. 162, 1807–1815 (2003).

    Article  CAS  Google Scholar 

  14. Hoornaert, I., Marynen, P., Goris, J., Sciot, R. & Baens, M. MAPK phosphatase DUSP16/MKP-7, a candidate tumor suppressor for chromosome region 12p12–13, reduces BCR-ABL-induced transformation. Oncogene 22, 7728–7736 (2003).

    Article  CAS  Google Scholar 

  15. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  Google Scholar 

  16. Kurz, D. J., Decary, S., Hong, Y. & Erusalimsky, J. D. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113, 3613–3622 (2000).

    CAS  PubMed  Google Scholar 

  17. Severino, J., Allen, R. G., Balin, S., Balin, A. & Cristofalo, V. J. Is beta-galactosidase staining a marker of senescence in vitro and in vivo? Exp. Cell Res. 257, 162–171 (2000).

    Article  CAS  Google Scholar 

  18. Yang, N. C. & Hu, M. L. A fluorimetric method using fluorescein di-beta-D-galactopyranoside for quantifying the senescence-associated beta-galactosidase activity in human foreskin fibroblast Hs68 cells. Anal. Biochem. 325, 337–343 (2004).

    Article  CAS  Google Scholar 

  19. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  Google Scholar 

  20. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  Google Scholar 

  21. Ruas, M. & Peters, G. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys. Acta. 1378, F115–F177 (1998).

    CAS  PubMed  Google Scholar 

  22. Sharpless, N. E. & DePinho, R. A. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9, 22–30 (1999).

    Article  CAS  Google Scholar 

  23. 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  Google Scholar 

  24. Shapiro, G. I. et al. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 55, 505–509 (1995).

    CAS  PubMed  Google Scholar 

  25. Masumoto, N. et al. P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix. Hum. Pathol. 34, 778–783 (2003).

    Article  CAS  Google Scholar 

  26. Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).

    Article  CAS  Google Scholar 

  27. Zhang, R. et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30 (2005).

    Article  CAS  Google Scholar 

  28. Malumbres, M. et al. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol. Cell. Biol. 20, 2915–2925 (2000).

    Article  CAS  Google Scholar 

  29. Nagane, M., Huang, H. J. & Cavenee, W. K. The potential of TRAIL for cancer chemotherapy. Apoptosis 6, 191–197 (2001).

    Article  CAS  Google Scholar 

  30. Giatromanolaki, A. et al. DEC1 (STRA13) protein expression relates to hypoxia- inducible factor 1-alpha and carbonic anhydrase-9 overexpression in non-small cell lung cancer. J. Pathol. 200, 222–228 (2003).

    Article  CAS  Google Scholar 

  31. Liu, X., Yue, P., Khuri, F. R. & Sun, S. Y. Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity. Cancer. Res. 65, 9169–9175 (2005).

    Article  CAS  Google Scholar 

  32. Yamada, K. & Miyamoto, K. Basic helix-loop-helix transcription factors, BHLHB2 and BHLHB3; their gene expressions are regulated by multiple extracellular stimuli. Front. Biosci. 10, 3151–3171 (2005).

    Article  CAS  Google Scholar 

  33. Barradas, M. et al. Identification of a candidate tumor-suppressor gene specifically activated during Ras-induced senescence. Exp. Cell Res. 273, 127–137 (2002).

    Article  CAS  Google Scholar 

  34. Hama, T. et al. Identification and molecular cloning of a novel brain-specific receptor protein that binds to brain injury-derived neurotrophic peptide. Possible role for neuronal survival. J. Biol. Chem. 276, 31929–31935 (2001).

    Article  CAS  Google Scholar 

  35. Brunk, U. T. & Terman, A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic. Biol. Med. 33, 611–619 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Mu, X. C. & Higgins, P. J. Differential growth state-dependent regulation of plasminogen activator inhibitor type-1 expression in senescent IMR-90 human diploid fibroblasts. J. Cell. Physiol. 165, 647–657 (1995).

    Article  CAS  Google Scholar 

  38. Mason, D. X., Jackson, T. J. & Lin, A. W. Molecular signature of oncogenic ras-induced senescence. Oncogene 23, 9238–9246 (2004).

    Article  CAS  Google Scholar 

  39. Chang, B. D. et al. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc. Natl Acad. Sci. USA 99, 389–394 (2002).

    Article  CAS  Google Scholar 

  40. Schmitt, C. A. Senescence, apoptosis and therapy – cutting the lifelines of cancer. Nature Rev. Cancer. 3, 286–295 (2003).

    Article  CAS  Google Scholar 

  41. Rebbaa, A., Zheng, X., Chou, P. M. & Mirkin, B. L. Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene 22, 2805–2811 (2003).

    Article  CAS  Google Scholar 

  42. Zheng, X., Chou, P. M., Mirkin, B. L. & Rebbaa, A. Senescence-initiated reversal of drug resistance: specific role of cathepsin L. Cancer Res. 64, 1773–1780 (2004).

    Article  CAS  Google Scholar 

  43. te Poele, 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).

    CAS  PubMed  Google Scholar 

  44. Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S. Y. & Wu, D. Y. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803 (2005).

    Article  CAS  Google Scholar 

  45. Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biol. 6, 168–170 (2004).

    Article  CAS  Google Scholar 

  46. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–645 (1999).

    Article  CAS  Google Scholar 

  47. 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  Google Scholar 

  48. Alcorta, D. A. et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA 93, 13742–13747 (1996).

    Article  CAS  Google Scholar 

  49. Afshari, C. A. et al. Investigation of the role of G1/S cell cycle mediators in cellular senescence. Exp. Cell Res. 209, 231–237 (1993).

    Article  CAS  Google Scholar 

  50. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    Article  CAS  Google Scholar 

  51. Tahara, H., Sato, E., Noda, A. & Ide, T. Increase in expression level of p21sdi1/cip1/waf1 with increasing division age in both normal and SV40-transformed human fibroblasts. Oncogene 10, 835–840 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Research at the laboratory of M.S. is funded by the Centro Nacional de Investigaciones Oncológicas (CNIO), the Spanish Ministry of Education and Science, and the European Union (INTACT and PROTEOMAGE projects).

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Correspondence to Manuel Serrano.

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Collado, M., Serrano, M. The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer 6, 472–476 (2006). https://doi.org/10.1038/nrc1884

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