SENESCENCIJA: DEFINICIJA, MEHANIZMI NASTANKA I DETEKCIJA U TKIVIMA
Sažetak
SAŽETAK: Senescencija predstavlja stanje koje se se definiše kao stabilno zaustavljanje ćelijskog ciklusa, u njegovoj G1 fazi, a kao odgovor na delovanje pregršt različitih okidača i njihovih kvantitaivnih i kvalitativnih karakteristika. Osim samog čina zaustavljanja ćelijskog ciklusa, proces senescencije je vrlo dinamičan, uključuje prateće i različite morfološke i intracelularne promene, promene u ekspresiji gena, epigenetske modifikacije, makromolekularna oštećenja, deregulaciju ćelijskog metabolizma i pojavu složenog proinflamatornog sekretornog fenotipa, moćnog modulatora i aktera brojnih biohemijskih dešavanja kako unutar samih senescentnih ćelija, tako i u njihovom okruženju. Osim pomenutog autokrinog, senescencija ima i parakrina dejstva na bližu i dalju okolinu. Decenijama unazad, u in vivo i in vitro uslovima, dokazani su i dokumentovani brojni, kako fiziološki tako i patološki uticaji senescencije na mnogobrojne procese u ljudskom telu. Upravo, onkogenima izazvan proces senescencije u in vitro uslovima, pokazao je značajan uticaj ovog procesa na supresiju tumorogeneze. Senescencija ne samo da zaustavlja proliferaciju i promociju tumorskih ćelija, već i značajno olakšava njihovo uklanjanje putem procesa imunološkog nadzora. Ukoliko imunološki nadzor doživi neuspeh, senescentne ćelije putem brojnih biohemijskih procesa dovode do stanja hronične inflamacije, mikrookruženja koje favorizuje incijaciju nastanka tumora, kasnije migraciju i angiogenezu, i na kraju metastaziranje i implantaciju tumorskih ćelija na udaljena mesta u ljudskom telu. Pored svega do sada navedenog senescencija se može inicirati i kao odgovor na genotoksični stres nakon primenjene terapije. Upravo ovaj momenat, pojave senescentnih ćelija nakon primenjene terapije i njihovo praćenje je ključno za otkrivanje potencijalnih premalignih događaja, kao i za primenu adekvatnih preventivnih i ranih terapijskih protokola.
Reference
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.