The Senescence-Associated Secretory Phenotype: History
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Wiktoria Monika Piskorz
,
Marzanna Cechowska-Pasko

Senescence is characterized by a senescence-associated secretory phenotype (SASP) that can have both beneficial and detrimental impact on cancer progression.

  • senescence
  • cancer
  • therapy
  • SASP

1. The Senescence-Associated Secretory Phenotype (SASP)

Senescent cells secrete a specific mixture of factors, including MMPs, cytokines, chemokines, growth factors, and angiogenic factors, which enable them to affect nearby cells. The composition of the molecules varies according to both the senescence inducer and the cell type. This secretome is known as the SASP [1][2]. The SASP promotes the spread of senescence and inflammation to surrounding cells in a paracrine way [3] and also triggers immune response to expel senescent cells [4]. Interestingly, senescent cells themselves are immune to the apoptotic and damaging influence of the SASP and they generate even more of the secretome in response [5].

2. The SASP Composition

The composition of SASP differs depending on the situation, which may be connected with its antagonistic effects. Early research on the SASP revealed the diversity of molecules secreted by senescent cells, among them chemokines and cytokines: C-X-C motif chemokine ligand 1 (CXCL1), C-C motif chemokine ligand 2 (CCL2), IL-6, interleukin 8 (IL-8), prosurvival factors like glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-binding proteins (IGFBPs) and growth modulators such as amphiregulin (AREG) [6]. Nowadays the composition of SASP is better known. Research shows that SASP also contains proteases, ceramides, extracellular matrix (ECM) molecules, signaling factors like bradykinins, hemostatic factors and damage-associated molecular patterns (DAMP) [7][8].
Cell type and senescence inducer seem to be major factors influencing the SASP composition [9]. Mitochondrial dysfunction-associated senescence (MiDAS) results in a distinct senescence response where the interleukin 1 (IL-1)-dependent proinflammatory impact does not occur [10]. The latest research shows that some of the SASP components are common in different cells and different types of senescence and may be some kind of core [8]. The composition of SASP depends on the passage of time as well. During OIS, transforming growth factor β (TGF-β) rich early immunosuppressive secretome turns into the SASP due to the fluctuation of neurogenic locus notch homolog protein 1 (NOTCH1) signaling [11]. What is more, expression of type I interferons (IFN) occurs in late OIS and is partly initiated by the reduction of LINE-1 retrotransposable elements [12]. This may partly explain the variability and sometimes contradiction in SASP effects. As can be seen, senescent cells’ secretome is complex and depends on a plethora of different factors. In order to better understand the SASP, further research is needed.

3. The SASP Beneficial Effects

Due to the differences in the quantity and nature of the molecules secreted by senescent cells, SASP may have both positive and negative effects on the organism. Beneficial and detrimental effects of some of the SASP components are presented in Table 1. Considering positives, senescent fibroblasts’ SASP, through platelet-derived growth factor AA (PDGF-AA) and cellular communication network factor 1 (CCN1), boost the skin regeneration process [13][14]. Moreover, the SASP reinforces tissue stemness and plasticity, prevents excessive tissue fibrosis, and restores homeostasis in liver fibrosis [15][16]. It can also promote the reprogramming of nearby cells if the tissue is damaged [17]. In addition, the SASP is responsible for the recruitment of immune cells, such as natural killer (NK) cells, T helper type 1 (Th1) cells and macrophages, which play a key role in initial preneoplastic cells elimination and prevent further carcinoma expansion [18]. Moreover, it can skew the polarity of macrophages to tumor-inhibiting state (M1), creating an antitumor environment [19]. Some elements of SASP, such as IL-6, IL-8, IGFBP7, and plasminogen activator inhibitor (PAI-1), support the senescent cell growth arrest [20].
Table 1. Beneficial and detrimental effects of the SASP components: CCN1 (cellular communication network factor 1), IL-6, IL-8, IGFBP7 (insulin-like growth factor-binding protein 7).
SASP Component Beneficial Effects Detrimental Effects
CCN1 p53 pathway activation → tumor suppression [21] EMT promotion → cancer progression [22][23]
Tissue regeneration [24][25] Cancer cells migration and metastasis [26][27][28][29]
Wound healing [24][25] Chemoresistance [30]
IL-6 Epithelial memory of inflammation → tissue regeneration in pancreas [31] MDSC activation → immunosuppression → lack of response to checkpoint inhibitor therapy [32]
↑ CCL4, CCL5, CCL17, CXCL10
→ T-cells activation [33]
Prevention of T-cells apoptosis [34][35]
Promotion of T-cells proliferation [36]		 Cancer development [31]
Inhibition of cancer cells apoptosis [37]
Promotion of tumor cells proliferation, angiogenesis and metastasis [37]
IL-8 Response to infection (phagocytosis, oxidative burst, neutrophil extracellular trap [38] Altering composition of immune cells in tumor microenvironment [38]
Activation of vascular endothelial cells → cells angiogenesis → ↑ proliferation, migration [39] Activation of vascular endothelial cells → cancer cells angiogenesis → cancer migration [40]
Infiltration of immune cells → tumor-reactive cytotoxic mechanism [41] Infiltration of neutrophils and MDSC → immunosuppression [38][42]
  ↑ growth factor secretion by tumor associated macrophages [40]
    Lower survival rate in tumor patients [42]
    EMT induction [38]
IGFBP7 ↑CDK inhibitors → cell cycle arrest → tumor suppression [43][44][45] Infiltration of immune cells in gastric cancer [46]
↑ E-cadherin, ↓ N-cadherin, ↓ Vimentin → EMT inhibition [47][48][49] Lower survival rate in gastric cancer patients [46]
  Higher survival rate in melanoma patients [50] Chemoresistance [51]

4. The Role of the SASP in Tumor-Promoting Environment

On the other hand, SASP-induced inflammation may negatively affect cells and even provoke cancer proliferation [20]. IL-1α, which is present in different types of senescence, influences cells in an autocrine way and generates inflammation. It activates NFκB, and enhances IL-6 and IL-8 secretion [52]. Additionally, IL-6 can promote cancer progression in a paracrine way by affecting the IL-6 receptor. There is activation of signal transducer and activator of transcription (STAT3), which leads to transcription of oncogenes and growth regulators, such as c-FOS, cyclin D1, c-MYC, mTOR and mammalian target of rapamycin complex 1 (mTORC1) [53]. It has been proven that as a result of the elimination of senescent cells, the level of proinflammatory cytokines, such as IL-1α, IL-6, and tumor necrosis factor α (TNFα), decreases [54][55], which prevents cancer relapse [56].
In hepatocellular carcinoma, CCL2 was observed to recruit immunosuppressive myeloid cells which restricted NK cells activity leading to further tumor progression [57]. CXCL1 is strongly expressed in both senescent cells and ovarian cancer samples [58]. Secretion of this chemokine can affect stromal cells in a paracrine way and promote tumor invasion and progression [59]. Many of the SASP factors (IL-1α, IL-6, IL-8, C-X-C motif chemokine ligand 12 (CXCL12), CCL2) are also common after anticancer therapy [60] and contribute to physical function decrease, fatigue, loss of appetite and cardiovascular morbidity [61][62][63]. Taking into consideration that senescence is an inherent element of cancer treatment (deliberately or not), it is believed that senescent cells may enhance some of the short-term and long-term side effects of anticancer therapy [59].
As mentioned before, elements of the SASP include growth factors, such as proangiogenic vascular endothelial growth factor (VEGF), which lead to cancer vascularization [64]. Furthermore, MMPs released by senescent cells promote cancer growth [65] and stimulate VEGF-dependent vascularization [66]. Moreover, the SASP is able to induce epithelial-to-mesenchymal transition (EMT), which promotes cancer vascularization and, consequently, tumor growth [2]. Research shows that senescent fibroblasts secretome may support tumor vascularization in xenograft transplants and enhance metastasis and proliferation of premalignant epithelial cells [64][67]. In co-culture composed of senescent lung fibroblasts (line WI38) and preneoplastic epithelial cells, the acceleration of proliferation was observed compared to co-culture with normative fibroblasts [6]. What is more, the enhanced-growth effect was not dependent on senescence inducer and did not occur when co-culturing senescent fibroblasts with normative epithelial cells [6]. Additionally, injection of senescent fibroblasts to breast cancer cells resulted in tumor growth acceleration [68]. What is more, the osteopontin (OPN) secretion increase was detected in senescent stromal cells of murine skin papilloma. Co-injection of OPN-deficient senescent cells was performed and the limitation of cancer growth was observed [69].
Milanovic et al. [70] conducted research to check the influence of chemotherapy-induced senescence on stem-cell-related properties in cancer. In senescent cells, enhancement of an adult tissue stem-cell signature, distinct stem-cell markers and Wnt signaling—a crucial factor in stem-cell restoration—have been observed. Furthermore, treating cells which escaped senescence and never senescent cells with a precise dose of chemotherapy resulted in accelerated and Wnt-dependent growth in previously senescent cells [70]. Wnt signaling is activated in therapy-induced senescence (TIS) and may contribute to higher cancer-initiating potential [70][71][72]. Additionally, in p53-regulatable models of acute leukemia, enhancement of senescence resulted in reprogramming of non-stem bulk leukemia cells to self-renewing stem cells that initiate leukemia [70]. On the other hand, recent studies on skin cancer cells indicated that senescent cells, in fact, promote tumor growth by, among others, P38MAPK and MAPK/extracellular signal-regulated kinase (ERK) up-regulation but do not induce the cancer development [73].

5. The SASP Regulation

The SASP regulation occurs at several levels, including secretion, mRNA stability, transcription and translation. Paracrine and autocrine feedbacks, which intensify secretion, are also important factors [20]. In control of the SASP regulation are, among others, cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) [58][68], DDR [6][74], or P38 mitogen-activated protein kinases (MAPK) [75]. All of them lead to NF-κB and CCAAT/enhancer-binding protein-β (C/EBPβ) activation, which directly controls the transcription of IL-6 and IL-8. These molecules in an autocrine way—through a feed-forward loop—increase the activity of NF-κB and C/EBPβ and intensify SASP [20]. Suppression of C/EBPβ transcriptional activity leads to a decrease in the SASP inflammatory activity [76]. Elimination of NF-κB and C/EBPβ results in IL-8 reduction, which affects OIS growth arrest [77][78]. As can be seen, there are visible connections between SASP, NF-κB activation, DDR and transcription factor GATA4 stabilization.

5.1. Epigenetic Regulation

The SASP can be also affected in an epigenetic way. Repression of transcriptional activator and oncoprotein MLL1 causes reduction of proliferative cell cycle regulators and inhibits SASP expression [79]. What is more, recruitment of bromodomain-containing protein 4 (BRD4) to superenhancers activated by senescence seems to be essential for the SASP induction [80]. Chromatic alterations, such as higher expression of macroH2A1 histone [81], reduced H3K9 histone dimethylation [82] or accumulation of H2AJ histone [83] also contribute to SASP regulation.
SASP induction may be provoked by inflammasomes, in particular inflammasome NLRP3, triggered by DAMP, which activates and processes IL-1β [3]. In OIS, inflammasome activation is caused by priming the toll-like receptor 2 (TLR2) by serum amyloids A1 and A2 [84]. A key role in the SASP induction is played by cytosolic DNA, derived from retrotransposable molecules (for instance LINE-1), cytosolic chromatin fragments (CCF) and mitochondrial DNA [1]. DDR and dysfunctional mitochondria promote formation of CCF and trigger the SASP [85]. The cGAS detects cytosolic DNA and synthesize cyclic GMP-AMP (cGAMP), which leads to STING activation [58][68][86]. STING activation results in TANK-binding kinase 1 (TBK1) secretion and IRF2 and NFκB activation, which stimulate IFN-I response [7]. Activation of P38MAPK stimulates activation of NF-κB as well [75].
MiDAS SASP is heavily influenced by metabolic abnormalities in NAD+ (nicotinamide adenine dinucleotide) to NADH ratios, which contribute to activation of P53 via influencing 5′AMP-activated protein kinase (AMPK) and enhance SASP [10]. Additionally, increased NAD+ salvage caused by a higher level of nicotinamide phosphoribosyltransferase (NAMPT) accelerates mitochondrial respiration and glycolysis in OIS and enhances SASP [87]. In the long run, all of these pathways lead to the induction of SASP.

5.2. Post-Transcriptional Control

A major factor in SASP regulation is the mTOR pathway. It has been proven that phosphorylation of 4EBP—translation repressor protein—mediated by mTOR, influences the translation of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) and IL-1α [52][88]. The stress-activated serine/threonine-protein kinase MAPKAPK2 activity leads to the inhibition of the mRNA-binding protein ZFP36L1, which directs the SASP components to degrade mRNA. The mTOR pathway can regulate the senescent secretome by influencing the stability of SASP mRNAs [88]. Furthermore, in OIS the TOR-autophagy spatial coupling compartment (TASCC) boosts autophagy and protein synthesis which result in the accumulation of SASP molecules [89]. What is more, the research indicates also that polypyrimidine tract-binding protein 1 (PTB1) can control senescent secretome via influencing an alternative splicing of genes taking part in intracellular trafficking (like EXOC7) [90].

5.3. DDR and the SASP

In order to induce cytokine secretion, constant DDR is usually needed [74]. Taking into consideration that deficiency of DDR regulators such as NBS1, CHK2 and ATM restrains cytokine expression caused by genotoxic stress, it can be presumed that these factors have a major impact on the SASP induction [91]. Research shows that ATM contributes to removal of macroH2A1.1 histone variant from SASP genes and so participates in SASP genes expression [81]. Activation of P16 protein may enhance senescence and inhibit cells proliferation, but is not sufficient to initiate SASP. On the other hand, P38MAPK activation is not only sufficient but also necessary to induce senescence and SASP even if DNA damage does not occur [75]. Additionally, P38 enhances the activity of NF-κB and, as a result, induces SASP transcripts expression [91]. Furthermore, P53 inhibition intensify SASP and create a proinflammatory environment, which provoke malignant transformation [74].
As can be observed, the factors related to DDR also influence the SASP, which confirms the thesis, that SASP is a complex phenomenon, dependent on many factors. It seems possible to regulate SASP by manipulating the DDR. It is important to search for more links between DDR and SASP, which may expand SASP regulation possibilities.

This entry is adapted from the peer-reviewed paper 10.3390/ijms231911082

References

  1. Gorgoulis, V.; Adams, P.D.; Alimonti, A.; Bennett, D.C.; Bischof, O.; Bishop, C.; Campisi, J.; Collado, M.; Evangelou, K.; Ferbeyre, G.; et al. Cellular Senescence: Defining a Path Forward. Cell 2019, 179, 813–827.
  2. Coppé, J.P.; Desprez, P.Y.; Krtolica, A.; Campisi, J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol. 2010, 5, 99–118.
  3. Acosta, J.C.; Banito, A.; Wuestefeld, T.; Georgilis, A.; Janich, P.; Morton, J.P.; Athineos, D.; Kang, T.W.; Lasitschka, F.; Andrulis, M.; et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 2013, 15, 978–990.
  4. Krizhanovsky, V.; Xue, W.; Zender, L.; Yon, M.; Hernando, E.; Lowe, S.W. Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. Cold Spring Harb. Symp. Quant. Biol. 2008, 73, 513–522.
  5. Wyld, L.; Bellantuono, I.; Tchkonia, T.; Morgan, J.; Turner, O.; Foss, F.; George, J.; Danson, S.; Kirkland, J.L. Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies. Cancers 2020, 12, 2134.
  6. Coppé, J.P.; Patil, C.K.; Rodier, F.; Sun, Y.; Muñoz, D.P.; Goldstein, J.; Nelson, P.S.; Desprez, P.Y.; Campisi, J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008, 6, 2853–2868.
  7. Birch, J.; Gil, J. Senescence and the SASP: Many therapeutic avenues. Genes Dev. 2020, 34, 1565–1576.
  8. Basisty, N.; Kale, A.; Jeon, O.H.; Kuehnemann, C.; Payne, T.; Rao, C.; Holtz, A.; Shah, S.; Sharma, V.; Ferrucci, L.; et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020, 18, e3000599.
  9. Rao, S.G.; Jackson, J.G. SASP: Tumor Suppressor or Promoter? Yes! Trends Cancer 2016, 2, 676–687.
  10. Wiley, C.D.; Velarde, M.C.; Lecot, P.; Liu, S.; Sarnoski, E.A.; Freund, A.; Shirakawa, K.; Lim, H.W.; Davis, S.S.; Ramanathan, A.; et al. Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 2016, 23, 303–314.
  11. Ito, Y.; Hoare, M.; Narita, M. Spatial and Temporal Control of Senescence. Trends Cell Biol. 2017, 27, 820–832.
  12. De Cecco, M.; Ito, T.; Petrashen, A.P.; Elias, A.E.; Skvir, N.J.; Criscione, S.W.; Caligiana, A.; Brocculi, G.; Adney, E.M.; Boeke, J.D.; et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019, 566, 73–78.
  13. Jun, J.I.; Lau, L.F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 2010, 12, 676–685.
  14. Demaria, M.; Ohtani, N.; Youssef, S.A.; Rodier, F.; Toussaint, W.; Mitchell, J.R.; Laberge, R.M.; Vijg, J.; Van Steeg, H.; Dollé, M.E.; et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 2014, 31, 722–733.
  15. Ritschka, B.; Storer, M.; Mas, A.; Heinzmann, F.; Ortells, M.C.; Morton, J.P.; Sansom, O.J.; Zender, L.; Keyes, W.M. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 2017, 31, 172–183.
  16. Krizhanovsky, V.; Yon, M.; Dickins, R.A.; Hearn, S.; Simon, J.; Miething, C.; Yee, H.; Zender, L.; Lowe, S.W. Senescence of activated stellate cells limits liver fibrosis. Cell 2008, 134, 657–667.
  17. Mosteiro, L.; Pantoja, C.; Alcazar, N.; Marión, R.M.; Chondronasiou, D.; Rovira, M.; Fernandez-Marcos, P.J.; Muñoz-Martin, M.; Blanco-Aparicio, C.; Pastor, J.; et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 2016, 354, aaf4445.
  18. Kang, T.W.; Yevsa, T.; Woller, N.; Hoenicke, L.; Wuestefeld, T.; Dauch, D.; Hohmeyer, A.; Gereke, M.; Rudalska, R.; Potapova, A.; et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 2011, 479, 547–551.
  19. Lujambio, A.; Akkari, L.; Simon, J.; Grace, D.; Tschaharganeh, D.F.; Bolden, J.E.; Zhao, Z.; Thapar, V.; Joyce, J.A.; Krizhanovsky, V.; et al. Non-cell-autonomous tumor suppression by p53. Cell 2013, 153, 449–460.
  20. Herranz, N.; Gil, J. Mechanisms and functions of cellular senescence. J. Clin. Investig. 2018, 128, 1238–1246.
  21. Tong, X.; O’Kelly, J.; Xie, D.; Mori, A.; Lemp, N.; McKenna, R.; Miller, C.W.; Koeffler, H.P. Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway. Oncogene 2004, 23, 4847–4855.
  22. Li, X.; Yuan, N.; Lin, L.; Yin, L.; Qu, Y. Targeting cysteine-rich angiogenic inducer-61 by antibody immunotherapy suppresses growth and migration of non-small cell lung cancer. Exp. Ther. Med. 2018, 16, 730–738.
  23. Zhu, Y.; Almuntashiri, S.; Han, Y.; Wang, X.; Somanath, P.R.; Zhang, D. The Roles of CCN1/CYR61 in Pulmonary Diseases. Int. J. Mol. Sci. 2020, 21, 7810.
  24. Feng, T.; Meng, J.; Kou, S.; Jiang, Z.; Huang, X.; Lu, Z.; Zhao, H.; Lau, L.F.; Zhou, B.; Zhang, H. CCN1-Induced Cellular Senescence Promotes Heart Regeneration. Circulation 2019, 139, 2495–2498.
  25. Kim, K.H.; Won, J.H.; Cheng, N.; Lau, L.F. The matricellular protein CCN1 in tissue injury repair. J. Cell Commun. Signal. 2018, 12, 273–279.
  26. Jandova, J.; Beyer, T.E.; Meuillet, E.J.; Watts, G.S. The matrix protein CCN1/CYR61 is required for alpha(V)beta5-mediated cancer cell migration. Cell Biochem. Funct. 2012, 30, 687–695.
  27. Sabile, A.A.; Arlt, M.J.; Muff, R.; Bode, B.; Langsam, B.; Bertz, J.; Jentzsch, T.; Puskas, G.J.; Born, W.; Fuchs, B. Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in mice. J. Bone Miner. Res. 2012, 27, 58–67.
  28. Fromigue, O.; Hamidouche, Z.; Vaudin, P.; Lecanda, F.; Patino, A.; Barbry, P.; Mari, B.; Marie, P.J. CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis. J. Bone Miner. Res. 2011, 26, 1533–1542.
  29. Huang, Y.T.; Lan, Q.; Lorusso, G.; Duffey, N.; Ruegg, C. The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget 2017, 8, 9200–9215.
  30. Banerjee, S.; Ghosh, A.; VonHoff, D.D.; Banerjee, S.K. Cyr61/CCN1 targets for chemosensitization in pancreatic cancer. Oncotarget 2019, 10, 3579–3580.
  31. Del Poggetto, E.; Ho, I.L.; Balestrieri, C.; Yen, E.Y.; Zhang, S.; Citron, F.; Shah, R.; Corti, D.; Diaferia, G.R.; Li, C.Y.; et al. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science 2021, 373, eabj0486.
  32. Weber, R.; Fleming, V.; Hu, X.; Nagibin, V.; Groth, C.; Altevogt, P.; Utikal, J.; Umansky, V. Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors. Front. Immunol. 2018, 9, 1310.
  33. McLoughlin, R.M.; Jenkins, B.J.; Grail, D.; Williams, A.S.; Fielding, C.A.; Parker, C.R.; Ernst, M.; Topley, N.; Jones, S.A. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc. Natl. Acad. Sci. USA 2005, 102, 9589–9594.
  34. Atreya, R.; Mudter, J.; Finotto, S.; Müllberg, J.; Jostock, T.; Wirtz, S.; Schütz, M.; Bartsch, B.; Holtmann, M.; Becker, C.; et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in crohn disease and experimental colitis in vivo. Nat. Med. 2000, 6, 583–588.
  35. Curnow, S.J.; Scheel-Toellner, D.; Jenkinson, W.; Raza, K.; Durrani, O.M.; Faint, J.M.; Rauz, S.; Wloka, K.; Pilling, D.; Rose-John, S.; et al. Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling. J. Immunol. 2004, 173, 5290–5297.
  36. Naugler, W.E.; Karin, M. The wolf in sheep’s clothing: The role of interleukin-6 in immunity, inflammation and cancer. Trends Mol. Med. 2008, 14, 109–119.
  37. Weber, R.; Groth, C.; Lasser, S.; Arkhypov, I.; Petrova, V.; Altevogt, P.; Utikal, J.; Umansky, V. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol. 2021, 359, 104254.
  38. David, J.M.; Dominguez, C.; Hamilton, D.H.; Palena, C. The IL-8/IL-8R Axis: A Double Agent in Tumor Immune Resistance. Vaccines 2016, 4, 22.
  39. Li, A.; Dubey, S.; Varney, M.L.; Dave, B.J.; Singh, R.K. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 2003, 170, 3369–3376.
  40. Waugh, D.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 2008, 14, 6735–6741.
  41. Ostrand-Rosenberg, S. Immune surveillance: A balance between protumor and antitumor immunity. Curr. Opin. Genet. Dev. 2008, 18, 11–18.
  42. Bakouny, Z.; Choueiri, T.K. IL-8 and cancer prognosis on immunotherapy. Nat. Med. 2020, 26, 650–651.
  43. Ruan, W.; Xu, E.; Xu, F.; Ma, Y.; Deng, H.; Huang, Q.; Lv, B.; Hu, H.; Lin, J.; Cui, J.; et al. IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis. Cancer Biol. Ther. 2007, 6, 354–359.
  44. Chen, D.; Yoo, B.K.; Santhekadur, P.K.; Gredler, R.; Bhutia, S.K.; Das, S.K.; Fuller, C.; Su, Z.Z.; Fisher, P.B.; Sarkar, D. Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma. Clin. Cancer Res. 2011, 17, 6693–6701.
  45. Zhang, L.; Lian, R.; Zhao, J.; Feng, X.; Ye, R.; Pan, L.; Wu, J.; Li, M.; Huang, Y.; Cai, J. IGFBP7 inhibits cell proliferation by suppressing AKT activity and cell cycle progression in thyroid carcinoma. Cell Biosci. 2019, 9, 44.
  46. Zhao, Q.; Zhao, R.; Song, C.; Wang, H.; Rong, J.; Wang, F.; Yan, L.; Song, Y.; Xie, Y. Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer. J. Cancer 2021, 12, 1343–1355.
  47. Li, Y.; Xi, Y.; Zhu, G.; Jia, J.; Huang, H.; Liu, Y.; Guo, Y.; Liu, L. Downregulated IGFBP7 facilitates liver metastasis by modulating epithelial-mesenchymal transition in colon cancer. Oncol. Rep. 2019, 42, 1935–1945.
  48. Watanabe, J.; Takiyama, Y.; Honjyo, J.; Makino, Y.; Fujita, Y.; Tateno, M.; Haneda, M. Role of IGFBP7 in Diabetic Nephropathy: TGF-β1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells. PLoS ONE 2016, 11, e0150897.
  49. Cai, X.; Wang, L.; Wang, X.; Hou, F. Silence of IGFBP7 suppresses apoptosis and epithelial mesenchymal transformation of high glucose induced-podocytes. Exp. Ther. Med. 2018, 16, 1095–1102.
  50. Wicklein, D.; Otto, B.; Suling, A.; Elies, E.; Lüers, G.; Lange, T.; Feldhaus, S.; Maar, H.; Schröder-Schwarz, J.; Brunner, G.; et al. CEACAM1 promotes melanoma metastasis and is involved in the regulation of the EMT associated gene network in melanoma cells. Sci. Rep. 2018, 8, 11893.
  51. Tang, X.; Mu, J.; Ma, L.; Tan, Q.; Wang, J.; Tan, J.; Zhang, S. IGFBP7 overexpression promotes acquired resistance to AZD9291 in non-small cell lung cancer. Biochem. Biophys. Res. Commun. 2021, 571, 38–45.
  52. Laberge, R.M.; Sun, Y.; Orjalo, A.V.; Patil, C.K.; Freund, A.; Zhou, L.; Curran, S.C.; Davalos, A.R.; Wilson-Edell, K.A.; Liu, S.; et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 2015, 17, 1049–1061.
  53. Fisher, D.T.; Appenheimer, M.M.; Evans, S.S. The two faces of IL-6 in the tumor microenvironment. Semin. Immunol. 2014, 26, 38–47.
  54. Baker, D.J.; Childs, B.G.; Durik, M.; Wijers, M.E.; Sieben, C.J.; Zhong, J.; Saltness, R.A.; Jeganathan, K.B.; Verzosa, G.C.; Pezeshki, A.; et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016, 530, 184–189.
  55. Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; van Willigenburg, H.; Feijtel, D.A.; et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 2017, 169, 132–147.e16.
  56. Demaria, M.; O’Leary, M.N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A.M.; et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017, 7, 165–176.
  57. Eggert, T.; Wolter, K.; Ji, J.; Ma, C.; Yevsa, T.; Klotz, S.; Medina-Echeverz, J.; Longerich, T.; Forgues, M.; Reisinger, F.; et al. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell 2016, 30, 533–547.
  58. Yang, H.; Wang, H.; Ren, J.; Chen, Q.; Chen, Z.J. cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. USA 2017, 114, E4612–E4620.
  59. Sieben, C.J.; Sturmlechner, I.; van de Sluis, B.; van Deursen, J.M. Two-Step Senescence-Focused Cancer Therapies. Trends Cell Biol. 2018, 28, 723–737.
  60. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444.
  61. Bhakta, N.; Liu, Q.; Yeo, F.; Baassiri, M.; Ehrhardt, M.J.; Srivastava, D.K.; Metzger, M.L.; Krasin, M.J.; Ness, K.K.; Hudson, M.M.; et al. Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: An analysis from the St Jude Lifetime Cohort Study. Lancet Oncol. 2016, 17, 1325–1334.
  62. Cupit-Link, M.C.; Kirkland, J.L.; Ness, K.K.; Armstrong, G.T.; Tchkonia, T.; LeBrasseur, N.K.; Armenian, S.H.; Ruddy, K.J.; Hashmi, S.K. Biology of premature ageing in survivors of cancer. ESMO Open 2017, 2, e000250.
  63. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  64. Coppé, J.P.; Kauser, K.; Campisi, J.; Beauséjour, C.M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 2006, 281, 29568–29574.
  65. Liu, D.; Hornsby, P.J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 2007, 67, 3117–3126.
  66. Woenne, E.C.; Lederle, W.; Zwick, S.; Palmowski, M.; Krell, H.; Semmler, W.; Mueller, M.M.; Kiessling, F. MMP inhibition blocks fibroblast-dependent skin cancer invasion, reduces vascularization and alters VEGF-A and PDGF-BB expression. Anticancer Res. 2010, 30, 703–711.
  67. 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 2001, 98, 12072–12077.
  68. Glück, S.; Guey, B.; Gulen, M.F.; Wolter, K.; Kang, T.W.; Schmacke, N.A.; Bridgeman, A.; Rehwinkel, J.; Zender, L.; Ablasser, A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 2017, 19, 1061–1070.
  69. Pazolli, E.; Luo, X.; Brehm, S.; Carbery, K.; Chung, J.J.; Prior, J.L.; Doherty, J.; Demehri, S.; Salavaggione, L.; Piwnica-Worms, D.; et al. Senescent stromal-derived osteopontin promotes preneoplastic cell growth. Cancer Res. 2009, 69, 1230–1239.
  70. Milanovic, M.; Fan, D.N.Y.; Belenki, D.; Däbritz, J.H.M.; Zhao, Z.; Yu, Y.; Dörr, J.R.; Dimitrova, L.; Lenze, D.; Monteiro Barbosa, I.A.; et al. Senescence-associated reprogramming promotes cancer stemness. Nature 2018, 553, 96–100.
  71. Nacarelli, T.; Fukumoto, T.; Zundell, J.A.; Fatkhutdinov, N.; Jean, S.; Cadungog, M.G.; Borowsky, M.E.; Zhang, R. NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer. Cancer Res. 2020, 80, 890–900.
  72. Basu, S.K.; Lee, S.; Salotti, J.; Basu, S.; Sakchaisri, K.; Xiao, Z.; Walia, V.; Westlake, C.J.; Morrison, D.K.; Johnson, P.F. Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets. Cancer Res. 2018, 78, 891–908.
  73. Alimirah, F.; Pulido, T.; Valdovinos, A.; Alptekin, S.; Chang, E.; Jones, E.; Diaz, D.A.; Flores, J.; Velarde, M.C.; Demaria, M.; et al. Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling. Cancer Res. 2020, 80, 3606–3619.
  74. Rodier, F.; Coppé, J.P.; Patil, C.K.; Hoeijmakers, W.A.; Muñoz, D.P.; Raza, S.R.; Freund, A.; Campeau, E.; Davalos, A.R.; Campisi, J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 2009, 11, 973–979.
  75. Freund, A.; Patil, C.K.; Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011, 30, 1536–1548.
  76. Hoare, M.; Ito, Y.; Kang, T.W.; Weekes, M.P.; Matheson, N.J.; Patten, D.A.; Shetty, S.; Parry, A.J.; Menon, S.; Salama, R.; et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 2016, 18, 979–992.
  77. Acosta, J.C.; O’Loghlen, A.; Banito, A.; Guijarro, M.V.; Augert, A.; Raguz, S.; Fumagalli, M.; Da Costa, M.; Brown, C.; Popov, N.; et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008, 133, 1006–1018.
  78. Kuilman, T.; Michaloglou, C.; Vredeveld, L.C.; Douma, S.; van Doorn, R.; Desmet, C.J.; Aarden, L.A.; Mooi, W.J.; Peeper, D.S. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008, 133, 1019–1031.
  79. Capell, B.C.; Drake, A.M.; Zhu, J.; Shah, P.P.; Dou, Z.; Dorsey, J.; Simola, D.F.; Donahue, G.; Sammons, M.; Rai, T.S.; et al. MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 2016, 30, 321–336.
  80. Tasdemir, N.; Banito, A.; Roe, J.S.; Alonso-Curbelo, D.; Camiolo, M.; Tschaharganeh, D.F.; Huang, C.H.; Aksoy, O.; Bolden, J.E.; Chen, C.C.; et al. BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov. 2016, 6, 612–629.
  81. Chen, H.; Ruiz, P.D.; McKimpson, W.M.; Novikov, L.; Kitsis, R.N.; Gamble, M.J. MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype. Mol. Cell 2015, 59, 719–731.
  82. Takahashi, A.; Imai, Y.; Yamakoshi, K.; Kuninaka, S.; Ohtani, N.; Yoshimoto, S.; Hori, S.; Tachibana, M.; Anderton, E.; Takeuchi, T.; et al. DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells. Mol. Cell 2012, 45, 123–131.
  83. Contrepois, K.; Coudereau, C.; Benayoun, B.A.; Schuler, N.; Roux, P.F.; Bischof, O.; Courbeyrette, R.; Carvalho, C.; Thuret, J.Y.; Ma, Z.; et al. Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat. Commun. 2017, 8, 14995.
  84. Hari, P.; Millar, F.R.; Tarrats, N.; Birch, J.; Quintanilla, A.; Rink, C.J.; Fernández-Duran, I.; Muir, M.; Finch, A.J.; Brunton, V.G.; et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci. Adv. 2019, 5, eaaw0254.
  85. Vizioli, M.G.; Liu, T.; Miller, K.N.; Robertson, N.A.; Gilroy, K.; Lagnado, A.B.; Perez-Garcia, A.; Kiourtis, C.; Dasgupta, N.; Lei, X.; et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020, 34, 428–445.
  86. Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangensteen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 2017, 550, 402–406.
  87. Nacarelli, T.; Lau, L.; Fukumoto, T.; Zundell, J.; Fatkhutdinov, N.; Wu, S.; Aird, K.M.; Iwasaki, O.; Kossenkov, A.V.; Schultz, D.; et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 2019, 21, 397–407.
  88. Herranz, N.; Gallage, S.; Mellone, M.; Wuestefeld, T.; Klotz, S.; Hanley, C.J.; Raguz, S.; Acosta, J.C.; Innes, A.J.; Banito, A.; et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 2015, 17, 1205–1217.
  89. Narita, M.; Young, A.R.; Arakawa, S.; Samarajiwa, S.A.; Nakashima, T.; Yoshida, S.; Hong, S.; Berry, L.S.; Reichelt, S.; Ferreira, M.; et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 2011, 332, 966–970.
  90. Georgilis, A.; Klotz, S.; Hanley, C.J.; Herranz, N.; Weirich, B.; Morancho, B.; Leote, A.C.; D’Artista, L.; Gallage, S.; Seehawer, M.; et al. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. Cancer Cell 2018, 34, 85–102.
  91. Di Micco, R.; Krizhanovsky, V.; Baker, D.; d’Adda di Fagagna, F. Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 2021, 22, 75–95.
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