SENESCENCE: DEFINITION, MECHANISMS OF OCCURENCE AND DETECTION IN TISSUES
Abstract
ABSTRACT: Cellular senescence represents a state, which is defined as a stable blockage of cellular cycle in the G1 phase, as an answer to multiple triggers and their qualitative and quantitative characteristics. Next to the blockage of the cellular cycle, the cellular senescence process is very dynamic. The process includes different morphological and intracellular changes, gene expression changes, epigenetic modification, macromolecular damages, cellular metabolism deregulation and appearance of complex proinflammation secretory phenotype, which is powerful modulator and contributor in many biochemical processes, not only in senescent cells, but also in their neighboring areas. Cellular senescence may have, next to the already mentioned autocrine, also a paracrine effect on the close and more distant surrounding. In past decades, in both in vivo and in vitro experiments, physiological and pathological influences of cellular senescence, on numerous processes in the human body, have been proven and documented. In particular, oncogene induced cellular senescence (under in vitro conditions), has shown significant influence of this process on the suppression of tumorigenesis. Cellular senescence does not only suppress proliferation and promotion of tumour cells, but it also facilitates their removal through the process of immunological surveillance. In case immunological surveillance is not successful, senescent cells may lead to the state of chronical inflammation of the microenvironment (through different biochemical processes), which leads to the initiation of the tumour formation, and later migration, angiogenesis, and final metastasis and implementation of tumour cells in remote parts of the human body. Next to all mentioned, cellular senescence may be initiated as an answer to a genotoxic stress, caused by the received therapy. Therefore, detection of senescence cells after the therapy, together with their monitoring is a key step to early detection of premalignant events, as well as to the application of adequate preventive and early therapeutic protocols.
References
1. Di Fagagna FD. Living on a break: Cellular senescence as a DNA-damage response. Nat. Rev. Cancer 2008; 8:512–522.
2. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25:585–621.
3. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965; 37:614–36.
4. Gorgoulis, V, Adams, PD, Alimonti A, Bennett D, Bischof O, Bishop C, et al. Cellular senescence: Defining a path forward. Cell 2019; 179:813–827.
5. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol Cell. 2004; 14:501–513.
6. De Keizer PL. The fountain of youth by targeting senescent cells? Trends Mol Med. 2017; 23:6–17.
7. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Senescence in premalignant tumours. Nature 2005; 436:642.
8. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005; 37:961–976.
9. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685–705.
10. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15:482–496.
11. Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. Programmed cell senescence during mammalian embryonic development. Cell. 2013; 155:1104–1118.
12. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, et al. Senescence as a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013; 155:1119–1130.
13. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA. 2001; 98(21):12072–12077.
14. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022; 22(6):340–355.
15. Galanos P, Vougas K, Walter D, Polyzos A, Maya-Mendoza A, Haagensen EJ, et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat Cell Biol. 2016; 18(7):777–789.
16. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120(4):513–522.
17. Laconi E, Marongiu F, DeGregori J. Cancer as a disease of old age: changing mutational and microenvironmental landscapes. Br J Cancer. 2020; 122(7):943–952.
18. Ewald JA, Desotelle JA, Wilding G, Jarrard DF. Therapy-induced senescence in cancer. J Natl Cancer Inst. 2010; 102(20):1536–1546.
19. Wang B, Kohli J, Demaria M. Senescent Cells in Cancer Therapy: Friends or Foes? Trends Cancer. 2020; 6(10):838–857.
20. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99–118.
21. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010; 16:238–246.
22. Parrinello S, Coppe JP, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci. 2005; 118:485–496.
23. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123:966–972.
24. Ancrile B, Lim KH, Counter CM. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 2007; 21:1714–1719.
25. Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 2004; 6:447–458.
26. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007; 8:729–740.
27. Sherr CJ, McCormick F. The RB and P53 pathways in cancer. Cancer Cell. 2002; 2:103–112.
28. Engeland K. Cell cycle regultation: p53-p21-RB signaling. Cell Death Differ. 2022; 29:946–960.
29. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev. 2019; 99(2):1047–1078.
30. Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY) 2017; 9(8):1867–1884.
31. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018; 28(6):436–453.
32. Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. Embo J. 2003; 22(16):4212–4222.