Abstract
Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent “proliferative arrest” commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions that must be addressed to fully understand the beneficial and detrimental impacts of cellular senescence during cancer therapy.
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References
Acosta JC, Gil J (2012) Senescence: a new weapon for cancer therapy. Trends Cell Biol 22:211–219
Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d’Adda di Fagagna F, Bernard D, Hernando E, Gil J (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–1018
Aird KM, Zhang R (2013) Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol Biol 965:185–196
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6:17–32
Ancrile B, Lim KH, Counter CM (2007) Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev 21:1714–1719
Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236
Balentien E, Mufson BE, Shattuck RL, Derynck R, Richmond A (1991) Effects of MGSA/GRO alpha on melanocyte transformation. Oncogene 6:1115–1124
Banito A, Gil J (2010) Induced pluripotent stem cells and senescence: learning the biology to improve the technology. EMBO Rep 11:353–359
Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, Pinho S, Silva JC, Azuara V, Walsh M, Vallier L, Gil J (2009) Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23:2134–2139
Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Orntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:633–637
Bavik C, Coleman I, Dean JP, Knudsen B, Plymate S, Nelson PS (2006) The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res 66:794–802
Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222
Ben-Porath I, Weinberg RA (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961–976
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665
Brenner AJ, Stampfer MR, Aldaz CM (1998) Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 17:199–205
Bryan TM, Reddel RR (1997) Telomere dynamics and telomerase activity in in vitro immortalised human cells. Eur J Cancer 33:767–773
Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740
Canino C, Mori F, Cambria A, Diamantini A, Germoni S, Alessandrini G, Borsellino G, Galati R, Battistini L, Blandino R, Facciolo F, Citro G, Strano S, Muti P, Blandino G, Cioce M (2012) SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 31:3148–3163
Chabner BA, Roberts TG Jr (2005) Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72
Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB (1999) A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 59:3761–3767
Chen Q, Ames BN (1994) Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA 91:4130–4134
Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci USA 92:4337–4341
Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730
Chen J, Huang X, Halicka D, Brodsky S, Avram A, Eskander J, Bloomgarden NA, Darzynkiewicz Z, Goligorsky MS (2006) Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53. Am J Physiol Heart Circ Physiol 290:H1575–H1586
Cheng S, Rodier F (2015) Manipulating senescence in health and disease: emerging tools. Cell Cycle 14:1613–1614
Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW (2011) Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136
Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8:18–30
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642
Coppe JP, Kauser K, Campisi J, Beausejour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574
Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868
Coppe JP, Desprez PY, Krtolica A, Campisi J (2010a) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118
Coppe JP, Patil CK, Rodier F, Krtolica A, Beausejour CM, Parrinello S, Hodgson JG, Chin K, Desprez PY, Campisi J (2010b) A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS One 5:e9188
Coppe JP, Rodier F, Patil CK, Freund A, Desprez PY, Campisi J (2011) Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286:36396–36403
Cristofalo VJ, Pignolo RJ (1993) Replicative senescence of human fibroblast-like cells in culture. Physiol Rev 73:617–638
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198
de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O (2009) Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4:1798–1806
Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dolle ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733
Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8:2540–2551
Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–642
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367
Doroshow JH, Kummar S (2014) Translational research in oncology–10 years of progress and future prospects. Nat Rev Clin Oncol 11:649–662
Dorr JR, Yu Y, Milanovic M, Beuster G, Zasada C, Dabritz JH, Lisec J, Lenze D, Gerhardt A, Schleicher K, Kratzat S, Purfurst B, Walenta S, Mueller-Klieser W, Graler M, Hummel M, Keller U, Buck AK, Dorken B, Willmitzer L, Reimann M, Kempa S, Lee S, Schmitt CA (2013) Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501:421–425
Drummond-Barbosa D (2008) Stem cells, their niches and the systemic environment: an aging network. Genetics 180:1787–1797
Elmore LW, Rehder CW, Di X, McChesney PA, Jackson-Cook CK, Gewirtz DA, Holt SE (2002) Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J Biol Chem 277:35509–35515
Ewald JA, Jarrard DF (2012) Decreased skp2 expression is necessary but not sufficient for therapy-induced senescence in prostate cancer. Transl Oncol 5:278–287
Ewald JA, Desotelle JA, Wilding G, Jarrard DF (2010) Therapy-induced senescence in cancer. J Natl Cancer Inst 102:1536–1546
Fenton M, Barker S, Kurz DJ, Erusalimsky JD (2001) Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol 21:220–226
Flanary BE, Sammons NW, Nguyen C, Walker D, Streit WJ (2007) Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 10:61–74
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105
Fridman AL, Tainsky MA (2008) Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27:5975–5987
Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14:355–365
Galanis E, Hartmann LC, Cliby WA, Long HJ, Peethambaram PP, Barrette BA, Kaur JS, Haluska PJ Jr, Aderca I, Zollman PJ, Sloan JA, Keeney G, Atherton PJ, Podratz KC, Dowdy SC, Stanhope CR, Wilson TO, Federspiel MJ, Peng KW, Russell SJ (2010) Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res 70:875–882
Ge H, Ni S, Wang X, Xu N, Liu Y, Wang X, Wang L, Song D, Song Y, Bai C (2012) Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer. PLoS One 7:e51821
Gilbert LA, Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143:355–366
Goldstein JC, Rodier F, Garbe JC, Stampfer MR, Campisi J (2005) Caspase-independent cytochrome c release is a sensitive measure of low-level apoptosis in cell culture models. Aging Cell 4:217–222
Goodwin EC, Yang E, Lee CJ, Lee HW, DiMaio D, Hwang ES (2000) Rapid induction of senescence in human cervical carcinoma cells. Proc Natl Acad Sci USA 97:10978–10983
Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43:405–413
Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514
Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J, Krek W (2001) Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci USA 98:5043–5048
Han Z, Wei W, Dunaway S, Darnowski JW, Calabresi P, Sedivy J, Hendrickson EA, Balan KV, Pantazis P, Wyche JH (2002) Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J Biol Chem 277:17154–17160
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460
Harrington EA, Bruce JL, Harlow E, Dyson N (1998) pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc Natl Acad Sci USA 95:11945–11950
Hayat MA (2013) Tumor dormancy, quiescence, and senescence : aging, cancer, and noncancer pathologies, vol 1. Springer, Dordrecht/New York
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
Hoenicke L, Zender L (2012) Immune surveillance of senescent cells–biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33:1123–1126
Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460:1132–1135
Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, Polyak K (2005) Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 37:899–905
Jackson JG, Pant V, Li Q, Chang LL, Quintas-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y, El-Naggar AK, Lozano G (2012) p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21:793–806
Jones KR, Elmore LW, Jackson-Cook C, Demasters G, Povirk LF, Holt SE, Gewirtz DA (2005) p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol 81:445–458
Joyner DE, Bastar JD, Randall RL (2006) Doxorubicin induces cell senescence preferentially over apoptosis in the FU-SY-1 synovial sarcoma cell line. J Orthop 24:1163–1169
Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–551
Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Izpisua Belmonte JC (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144
Koch CM, Reck K, Shao K, Lin Q, Joussen S, Ziegler P, Walenda G, Drescher W, Opalka B, May T, Brummendorf T, Zenke M, Saric T, Wagner W (2013) Pluripotent stem cells escape from senescence-associated DNA methylation changes. Genome Res 23:248–259
Kortlever RM, Higgins PJ, Bernards R (2006) Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 8:877–884
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Investig 114:1299–1307
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479
Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32:355–357
Kurz DJ, Decary S, Hong Y, Erusalimsky JD (2000) Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113(Pt 20):3613–3622
Kwong J, Chen M, Lv D, Luo N, Su W, Xiang R, Sun P (2013) Induction of p38delta expression plays an essential role in oncogenic ras-induced senescence. Mol Cell Biol 33:3780–3794
Laberge RM, Awad P, Campisi J, Desprez PY (2012) Epithelial-mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron 5:39–44
Laberge RM, Adler D, DeMaria M, Mechtouf N, Teachenor R, Cardin GB, Desprez PY, Campisi J, Rodier F (2013) Mitochondrial DNA damage induces apoptosis in senescent cells. Cell Death Dis 4:e727
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, Kleijer WJ, DiMaio D, Hwang ES (2006) Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5:187–195
Leong WF, Chau JF, Li B (2009) p53 Deficiency leads to compensatory up-regulation of p16INK4a. Mol Cancer Res 7:354–360
Li Q, Tainsky MA (2011) Epigenetic silencing of IRF7 and/or IRF5 in lung cancer cells leads to increased sensitivity to oncolytic viruses. PLoS One 6:e28683
Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, Blasco MA, Serrano M (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12:3008–3019
Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, Yang WL, Wang J, Egia A, Nakayama KI, Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PP (2010) Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464:374–379
Liu D, Hornsby PJ (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117–3126
Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A (2013) Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-kappaB impairs this drug-induced senescence. EMBO Mol Med 5:149–166
Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18:306–319
Malaquin N, Carrier-Leclerc A, Dessureault M, Rodier F (2015) DDR-mediated crosstalk between DNA-damaged cells and their microenvironment. Front Genet 6:94
Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153
Marxer M, Ma HT, Man WY, Poon RY (2014) p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases. Oncogene 33:3550–3560
Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724
Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA (2000) Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 60:2562–2566
Muller PA, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15:2–8
Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496
Muntoni A, Reddel RR (2005) The first molecular details of ALT in human tumor cells. Human molecular genetics. 14 Spec No. 2:R191–196
Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716
Newton AC (1995) Protein kinase C: structure, function, and regulation. J Biol Chem 270:28495–28498
Nickoloff BJ, Lingen MW, Chang BD, Shen M, Swift M, Curry J, Bacon P, Bodner B, Roninson IB (2004) Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. Cancer Res 64:2956–2961
Nielsen GP, Stemmer-Rachamimov AO, Ino Y, Moller MB, Rosenberg AE, Louis DN (1999) Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. Am J Pathol 155:1879–1884
Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, Matsumoto K, Nakamura T, Tanaka M (2004) Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res 64:3215–3222
Oliva JL, Caino MC, Senderowicz AM, Kazanietz MG (2008) S-Phase-specific activation of PKC alpha induces senescence in non-small cell lung cancer cells. J Biol Chem 283:5466–5476
Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190
Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59:5002–5011
Orimo A, Weinberg RA (2006) Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5:1597–1601
Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M (2006) Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25:176–185
Papp B, Plath K (2011) Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res 21:486–501
Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747
Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118:485–496
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347
Price JS, Waters JG, Darrah C, Pennington C, Edwards DR, Donell ST, Clark IM (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell 1:57–65
Qian Y, Zhang J, Yan B, Chen X (2008) DEC1, a basic helix-loop-helix transcription factor and a novel target gene of the p53 family, mediates p53-dependent premature senescence. J Biol Chem 283:2896–2905
Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547–556
Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979
Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppe JP, Campeau E, Beausejour CM, Kim SH, Davalos AR, Campisi J (2011) DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 124:68–81
Rodriguez-Menocal L, Pham SM, Mateu D, St-Pierre M, Wei Y, Pestana I, Aitouche A, Vazquez-Padron RI (2010) Aging increases p16 INK4a expression in vascular smooth-muscle cells. Biosci Rep 30:11–18
Ross AL, Sanchez MI, Grichnik JM (2011) Nevus senescence. ISRN Dermatol 2011:642157
Satyanarayana A, Greenberg RA, Schaetzlein S, Buer J, Masutomi K, Hahn WC, Zimmermann S, Martens U, Manns MP, Rudolph KL (2004) Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol Cell Biol 24:5459–5474
Schadendorf D, Moller A, Algermissen B, Worm M, Sticherling M, Czarnetzki BM (1993) IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 151:2667–2675
Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346
Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D (2003) Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37:653–664
Schwarze SR, Fu VX, Desotelle JA, Kenowski ML, Jarrard DF (2005) The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. Neoplasia 7:816–823
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602
Sharpless NE, DePinho RA (2004) Telomeres, stem cells, senescence, and cancer. J Clin Investig 113:160–168
Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999) Microarray analysis of replicative senescence. Curr Biol 9:939–945
Sin S, Kim SY, Kim SS (2012) Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. Int J Oncol 41:1669–1674
Soussi T, Wiman KG (2007) Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 12:303–312
Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458
Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130
Su X, Cho MS, Gi YJ, Ayanga BA, Sherr CJ, Flores ER (2009) Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf. EMBO J 28:1904–1915
Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359–1368
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62:1876–1883
Tsuji T, Aoshiba K, Nagai A (2006) Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 174:886–893
Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Park SH, Thompson T, Karsenty G, Bradley A, Donehower LA (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53
Vasile E, Tomita Y, Brown LF, Kocher O, Dvorak HF (2001) Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J 15:458–466
Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141
Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132:363–374
Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, Sun P (2002) Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 22:3389–3403
Weiland T, Lampe J, Essmann F, Venturelli S, Berger A, Bossow S, Berchtold S, Schulze-Osthoff K, Lauer UM, Bitzer M (2014) Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses. Int J Cancer (Journal international du cancer) 134:235–243
Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM (2000) Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways. EMBO J 19:5762–5771
Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, Rudolph KL (2002) Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 16:935–942
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660
Yamakoshi K, Takahashi A, Hirota F, Nakayama R, Ishimaru N, Kubo Y, Mann DJ, Ohmura M, Hirao A, Saya H, Arase S, Hayashi Y, Nakao K, Matsumoto M, Ohtani N, Hara E (2009) Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. J Cell Biol 186:393–407
Yang G, Rosen DG, Zhang Z, Bast RC Jr, Mills GB, Colacino JA, Mercado-Uribe I, Liu J (2006) 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
Yang F, Jove V, Xin H, Hedvat M, Van Meter TE, Yu H (2010) Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. Mol Cancer Res 8:35–45
Yaswen P, MacKenzie KL, Keith WN, Hentosh P, Rodier F, Zhu J, Firestone GL, Matheu A, Carnero A, Bilsland A, Sundin T, Honoki K, Fujii H, Georgakilas AG, Amedei A, Amin A, Helferich B, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Niccolai E, Aquilano K, Ashraf SS, Nowsheen S, Yang X (2015) Therapeutic targeting of replicative immortality. Semin Cancer Biol. doi:10.1016/j.semcancer.2015.03.007
Zhang H, Herbert BS, Pan KH, Shay JW, Cohen SN (2004) Disparate effects of telomere attrition on gene expression during replicative senescence of human mammary epithelial cells cultured under different conditions. Oncogene 23:6193–6198
Zhang J, Pickering CR, Holst CR, Gauthier ML, Tlsty TD (2006) p16INK4a modulates p53 in primary human mammary epithelial cells. Cancer Res 66:10325–10331
Zhu Y, Xu L, Zhang J, Hu X, Liu Y, Yin H, Lv T, Zhang H, Liu L, An H, Liu H, Xu J, Lin Z (2013) Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells. Cancer Sci 104:1052–1061
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–658
Zindy F, Quelle DE, Roussel MF, Sherr CJ (1997) Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15:203–211
Zurgil U, Ben-Ari A, Atias K, Isakov N, Apte R, Livneh E (2014) PKCeta promotes senescence induced by oxidative stress and chemotherapy. Cell Death Dis 5:e1531
Acknowledgments
We thank members of the Rodier laboratory for valuable comments and discussions and Suzana Anjos for language editing. This work was supported by the Institut du Cancer de Montréal and by grants from the Canadian Institute for Health Research [MOP114962] and the Terry Fox Research Institute [1030] to F.R. F.R. is supported by a Fonds de Recherche Québec Santé junior I career award [22624].
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Gonzalez, L.C., Ghadaouia, S., Martinez, A. et al. Premature aging/senescence in cancer cells facing therapy: good or bad?. Biogerontology 17, 71–87 (2016). https://doi.org/10.1007/s10522-015-9593-9
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DOI: https://doi.org/10.1007/s10522-015-9593-9