Senescent Cells in Cancer Therapy: Friends or Foes?

Cellular senescence is a common outcome of various anticancer interventions.Senescence-associated secretory phenotypes (SASPs) have pro-tumorigenic functions.Evidence exists of increased cellular senescence in patients treated for various types of cancer.Therapy-induced senescence can cause cancer metastasis and relapse and several adverse reactions to cancer treatments.Pharmacological interference with detrimental senescence might be considered to improve the efficacy of cancer treatments and improve the life quality of treated patients. Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are able to potentiate various aspects of tumorigenesis, including proliferation, metastasis, and immunosuppression. Moreover, the accumulation and persistence of therapy-induced senescent cells can promote tissue dysfunction and the early onset of various age-related symptoms in treated cancer patients. Here, we review in detail the mechanisms by which cellular senescence contributes to cancer development and the side effects of cancer therapies. We also review how pharmacological interventions to eliminate senescent cells or inhibit SASP production can mitigate these negative effects and propose therapeutic strategies based on the age of the patient. Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are able to potentiate various aspects of tumorigenesis, including proliferation, metastasis, and immunosuppression. Moreover, the accumulation and persistence of therapy-induced senescent cells can promote tissue dysfunction and the early onset of various age-related symptoms in treated cancer patients. Here, we review in detail the mechanisms by which cellular senescence contributes to cancer development and the side effects of cancer therapies. We also review how pharmacological interventions to eliminate senescent cells or inhibit SASP production can mitigate these negative effects and propose therapeutic strategies based on the age of the patient. Cellular senescence is a multifaceted and highly heterogeneous state characterized by generally irreversible growth arrest, elevated lysosomal activity, resistance to apoptotic stimuli, deregulated metabolism, persistent DNA damage, and elevated secretion of chemokines, cytokines and growth factors [1.Gorgoulis V. et al.Cellular senescence: defining a path forward.Cell. 2019; 179: 813-827Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar]. The stability of the cell cycle arrest relies on the cyclin-dependent kinase (CDK) inhibitors p16 and p21 – often regulated by the master tumor suppressor protein p53 – and their elevated expression serves as a marker for senescence detection [2.Hernandez-Segura A. et al.Hallmarks of cellular senescence.Trends Cell Biol. 2018; 28: 436-453Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar]. Another important feature of virtually all senescent cells is increased activation of senescence-associated (SA)-β-galactosidase, a lysosomal enzyme whose activity is dispensable for the senescence phenotype [3.Lee B. et al.Senescence-associated β-galactosidase is lysosomal β-galactosidase.Aging Cell. 2006; 5: 187-195Crossref PubMed Scopus (496) Google Scholar]. Especially in cancer studies, SA-β-galactosidase activity is often used as a unique surrogate marker to define a senescent state. However, SA-β-galactosidase activity can be observed in some non-senescent contexts such as hair follicles and sebaceous glands in the skin [4.Dimri G. Medrano E. A biomarker that identifies senescent human cells in culture and in aging skin in vivo.Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9363-9367Crossref PubMed Scopus (4984) Google Scholar]. It can also be detected in activated macrophages, including those infiltrating tumors, which may cause difficulties in the precise identification of senescent cancer cells in a tumor microenvironment in vivo [5.Hall B. et al.p16Ink4a and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli.Aging. 2017; 9: 1867-1884Crossref PubMed Scopus (0) Google Scholar,6.Sharpless N. Sherr C. Forging a signature of in vivo senescence.Nat. Rev. Cancer. 2015; 15: 397-408Crossref PubMed Scopus (318) Google Scholar]. Recent studies have demonstrated that senescent cells are able to resist proapoptotic stresses via the upregulation of antiapoptotic mechanisms. Specific regulators of this function seem highly cell-type and stress dependent, making their use as markers for senescence challenging [7.Yosef R. et al.Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL.Nat. Commun. 2016; 7: 11190Crossref PubMed Scopus (250) Google Scholar,8.Zhu Y. et al.Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors.Aging Cell. 2016; 15: 428-435Crossref PubMed Scopus (244) Google Scholar]. On the same line, while metabolism is perturbed in senescent cells, no clear common metabolic mechanism that can be exploited for senescence identification has been demonstrated. A common trigger for senescence induction is the activation of a persistent DNA damage response (DDR), making the DDR markers γ-H2AX and 53BP1 focus staining widely used markers for senescent cells. These proteins are also components of DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) [9.Rodier F. et al.DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion.J. Cell Sci. 2010; 124: 68-81Crossref PubMed Scopus (259) Google Scholar]. Moreover, senescence-associated heterochromatin foci (SAHFs), which are regions of condensed chromatin containing heterochromatin protein 1 and the histone H2A variant macroH2A and HMGA proteins, are observed in human, but not mouse, senescent cells [10.Zhang R. et al.Molecular dissection of formation of senescence-associated heterochromatin foci.Mol. Cell. Biol. 2007; 27: 2343-2358Crossref PubMed Scopus (248) Google Scholar]. One of the most variable senescence-associated phenotypes is the SASP, a transcriptional program for genes encoding secreted proteins that is a consequence of persistent DDR [11.Rodier F. et al.Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.Nat. Cell Biol. 2009; 11: 973-979Crossref PubMed Scopus (1102) Google Scholar] and mediated by the NF-κB [12.Chien Y. et al.Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.Gene Dev. 2011; 25: 2125-2136Crossref PubMed Scopus (0) Google Scholar], p38 MAPK [13.Freund A. et al.p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.EMBO J. 2011; 30: 1536-1548Crossref PubMed Scopus (418) Google Scholar], and C/EBPβ pathways [14.Kuilman T. et al.Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.Cell. 2008; 133: 1019-1031Abstract Full Text Full Text PDF PubMed Scopus (1071) Google Scholar]. The SASP is enriched in proinflammatory factors, such as IL-6, IL-8, CXCL1, CCL2, CCL5, and matrix metalloproteinase (MMP) 3 [15.Coppé J. et al.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoS Biol. 2008; 6e301Crossref PubMed Scopus (1707) Google Scholar], which can be used as markers for DNA damage-induced senescence. The senescence-associated growth arrest is seen as a potent strategy to interfere with cancer progression. Moreover, SASP factors can stimulate immunosurveillance mechanisms and potentiate the tumor suppressive function of senescent cells by guiding the immune system to mount anticancer responses. For this reason, features of senescent cells serve as common biomarkers to evaluate the efficacy of anticancer treatments. While cellular senescence is an oncosuppressive mechanism and a potent anticancer therapeutic strategy (for more information see [16.Collado M. et al.Tumour biology: senescence in premalignant tumours.Nature. 2005; 436: 642Crossref PubMed Scopus (1035) Google Scholar,17.te Poele R.H. et al.DNA damage is able to induce senescence in tumor cells in vitro and in vivo.Cancer Res. 2002; 62: 1876-1883PubMed Google Scholar]), several issues exist with the generation and persistence of therapy-induced senescent cells. First, the SASP can play detrimental roles by protecting tumors from immune clearance, providing growth factors, and enhancing angiogenesis. Second, because most anticancer treatments are administered via systemic routes, many senescent cells are generated in nontumor areas [18.Ewald J. et al.Therapy-induced senescence in cancer.J. Natl. Cancer Inst. 2010; 102: 1536-1546Crossref PubMed Scopus (358) Google Scholar]. This excessive accumulation can have substantial side effects and accelerate the onset and progression of chronic diseases such as cardiovascular, fibrotic, and neurodegenerative diseases, which normally are observed at advanced age [19.Campisi J. et al.Cellular senescence: a link between cancer and age-related degenerative disease?.Semin. Cancer Biol. 2011; 21: 354-359PubMed Google Scholar]. Third, because cancer cells are genomically unstable, they can bypass the senescence growth arrest and restore aggressive and uncontrolled proliferation. This review analyzes these points and discusses the potential strategies to limit the detrimental effects of therapy-induced senescent cells. A significant number of commonly used cancer interventions have been associated with the induction of cellular senescence in either tumor or nontumor cells and tissues (Table 1, Key Table). These senescence-inducing interventions can be categorized into five families: chemotherapy, radiotherapy, CDK4/6 inhibitors, epigenetic modulators, and immunotherapy.Table 1Key Table. Summary of Senescence-Inducing Cancer TherapyCategoryDrugCell typeMarkerTreatmentRefsChemotherapyDoxorubicinFibrosarcoma (HT1080)(i) Elevated SA-β-galactosidase activities(ii) G1 cell cycle arrest(iii) Increased micronuclei formation40 nM for 4 days[38.Chang B. et al.A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents.Cancer Res. 1999; 59: 3761-3767PubMed Google Scholar]Breast cancer (MCF7)(i) Elevated SA-β-galactosidase activities(ii) Increased micronuclei formation50 nM for 2 daysBreast cancer (MDA-MB-231)(i) Increased micronuclei formation50 nM for 2 daysColon cancer (HCT116)(i) Elevated SA-β-galactosidase activities(ii) G1 cell cycle arrest(iii) Increased micronuclei formation50 nM for 4 daysProstate cancer (PC3)(i) G1 cell cycle arrest(ii) Increased micronuclei formation100 nM for 4 daysProstate cancer (LNCaP)(i) Elevated SA-β-galactosidase activities(ii) G1 cell cycle arrest(iii) Increased micronuclei formation100–500 nM for 4 daysOvarian cancer (A2780)(i) Elevated SA-β-galactosidase activities(ii) G1 cell cycle arrest(iii) Increased micronuclei formation20–50 nM for 4 daysGlioma (U251)(i) Elevated SA-β-galactosidase activities(ii) Increased micronuclei formation200 nM for 4 daysLeukemia (K562)(i) Elevated SA-β-galactosidase activities50 nM for 4 days[22.Yang M. et al.Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells.PLoS One. 2012; 7e37205Crossref PubMed Scopus (31) Google Scholar]Melanoma (SK-MEL-103)(i) Elevated SA-β-galactosidase activities1 μM for 7 days[32.Muñoz-Espín D. et al.A versatile drug delivery system targeting senescent cells.EMBO Mol. Med. 2018; 10e9355Crossref PubMed Scopus (36) Google Scholar]Vascular smooth muscle cells(i) Elevated SA-β-galactosidase activities(ii) Morphology (enlarged)(iii) G1 cell cycle arrest(iv) p53/p21 upregulation(v) p16 upregulation(vi) SASP induction(vii) Increased DDR100 nM for 24 h[135.Bielak-Zmijewska A. et al.A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.Biogerontology. 2014; 15: 47-64Crossref PubMed Scopus (46) Google Scholar]Prostate stromal cells (PSC27)(i) Elevated SA-β-galactosidase activities(ii) Reduced BrdU incorporation10 μM for 24 h[136.Chen F. et al.Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance.Nat. 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Cancer Res. 2016; 22: 2000-2008Crossref PubMed Scopus (76) Google Scholar]Endothelial cell (HUVEC)(i) Elevated SA-β-galactosidase activities2.5 or 5 nM for 24 h[24.Ota H. et al.Sirolimus and everolimus induce endothelial cellular senescence via sirtuin 1 down-regulation therapeutic implication of cilostazol after drug-eluting stent implantation.J. Am. Coll. Cardiol. 2009; 53: 2298-2305Crossref PubMed Google Scholar]Immortalized skin fibroblasts (hTERT-BJ)(i) Elevated SA-β-galactosidase activities(ii) p53 upregulation(iii) IL-6 upregulation100 nM for 24 to 72 h[141.Peiris-Pagès M. et al.Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog–GLI signalling in breast cancer cells.Oncotarget. 2015; 6: 10728-10745Crossref PubMed Google Scholar]Human bone marrow mononuclear cells (hBMNCs)(i) Reduced proliferation(ii Increased DDR(iii) Elevated SA-β-galactosidase activities0.03, 0.3, 1 μM for 5 days[29.Hu W. et al.Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies.Clin. Cancer Res. 2016; 22: 2000-2008Crossref PubMed Scopus (76) Google Scholar]Mouse dermal fibroblast(i) Elevated SA-β-galactosidase activities(ii) Reduced population doubling(iii) p16 upregulation(iv) LMNB1 reduction(v) SASP induction(vi) Increased DDR50 nM for 24 h or 48 h[30.Demaria M. et al.Cellular senescence promotes adverse effects of chemotherapy and cancer relapse.Cancer Discov. 2017; 7: 165-176Crossref PubMed Scopus (281) Google Scholar]Reporter p16-3MR mice(i) Increased bioluminescence(ii) p16 upregulation in skin and lung10 mg/kg for 3 consecutive daysBleomycinLung cancer (A549)(i) Elevated SA-β-galactosidase activities(ii) Reduced BrdU incorporation(iii) Increased cell size(iv) p53/p21 upregulation50 μg/ml for 120 h50 mU/ml for 48 h0.05–50 μg/ml for 72 h[33.Qiu T. et al.PTEN loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation.Aging (Albany NY). 2019; 11: 7492-7509Crossref PubMed Scopus (4) Google Scholar,142.Linge A. et al.Downregulation of caveolin-1 affects bleomycin-induced growth arrest and cellular senescence in A549 cells.Int. 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