Non-Cell-Autonomous Tumor Suppression by p53
Open accessAbstract
The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor-suppressive program that involves stable cell-cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function.
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This immune response is mediated by SASP components and by direct contact between immune cells and senescent cells.
“This response is mediated by SASP components and by the direct interaction between immune cells and senescent cells153,156–158.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [153]
The Results sections on SASP and macrophage function show that SASP factors affect macrophage targeting of senescent hepatic stellate cells. The co-culture experiments show macrophages eliminating those cells, but do not establish that direct cell-to-cell contact mediates the response. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe SASP of senescent hepatic stellate cells participates in fibrotic scar degradation and restores tissue homeostasis in liver fibrosis.
“Senescent fibroblasts contribute to wound healing (Demaria et al. 2014), and the SASP of senescent hepatic stellate cells (HSCs) participates in fibrotic scar degradation and restores tissue homeostasis in liver fibrosis (Lujambio et al. 2013).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Lujambio et al. 2013
The Introduction describes senescent HSCs as part of a tissue-homeostatic mechanism that limits fibrosis and facilitates its resolution, including through SASP effects on the extracellular matrix and immune surveillance. The Discussion says HSC p53 activity helps maintain organ integrity through SASP. Neither passage establishes fibrotic-scar degradation specifically or shows that tissue homeostasis is restored, so the claim overstates those outcomes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe senescence-associated phenotype identified with secretion of pro-tumorigenic cytokines and chemokines can be restrained or qualitatively modified by p53 in several cell types in mouse.
“This senescence-associated phenotype identified with secretion of pro-tumorigenic cytokines and chemokines can be restrained or qualitatively modified by p53 in several cell types in mouse [39, 41].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [41]
The Results and Discussion report that p53 qualitatively changes cytokine and chemokine secretion in murine hepatic stellate cells, promoting an anti-tumorigenic microenvironment. The Discussion also mentions an earlier report of p53 suppressing secretion in senescent fibroblasts, but this paper does not establish the claimed effect in several mouse cell types. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSenescent cells are surveilled by several innate and adaptive immune cell types, including NK cells, T cells, and macrophages.
“Senescent cells are indeed subjected to immunosurveillance by multiple components of innate and adaptive immunity, including NK cells, T cells and macrophages145,151,153–156.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [153]
In a fibrosis-associated liver cancer model, the SASP can contribute to an anti-tumor microenvironment by skewing macrophage polarization to a tumor-inhibiting M1 state.
“Moreover, in a fibrosis-associated liver cancer model, the SASP can contribute to an anti-tumor microenvironment by skewing macrophage polarization to a tumor-inhibiting M1 state (Lujambio et al. 2013).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Lujambio et al. 2013
p53 cooperates with the NF-κB pathway to regulate SASP factors that can activate macrophages to form a tumour-suppressive microenvironment.
“p53 cooperates with the NF- κB pathway to regulate SASP factors that can activate macrophages to form a tumour- suppressive microenvironment 147,148 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [148]
Factors secreted by senescent cells can stimulate the immune system to suppress tumorigenesis and promote repair of damaged tissues.
“these secreted factors can stimulate the immune system to both suppress tumorigenesis and promote optimal repair of damaged tissues when senescent cells are removed after their beneficial actions (15–17).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [16]
In mHSCs from adult mouse with Dox-inducible shp53, upon Dox withdrawal senescence is induced by re-expression of p53 and mHSCs show increase in markers of senescence concomitant with accumulation of Itgb3.
“Upon Dox withdrawal, senescence is induced by re-expression of p53 and mHSCs showed an increase in a number of markers of senescence (Figure S6A), concomitant with the accumulation of Itgb3”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Lujambio et al., 2013
The SASP of senescent activated HSCs attracts innate immune cells that eliminate these cells and help resolve fibrosis.
“The SASP also attracts innate immune cells that in turn eliminate the senescent HSCs and facilitate the resolution of fibrosis 94,120”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [94]
In a CCl4-induced mouse liver fibrosis model, activated hepatic stellate cells become senescent and display a SASP including extracellular matrix degrading enzymes and proinflammatory cytokines.
“activated HSCs become senescent, exhibiting a typical SASP, including the expression of extracellular matrix degrading enzymes and proinflammatory cytokines.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [94]
Cells that could not become senescent due to p53 deletion were not targeted by macrophages.
“Conversely, cells that could not become senescent due to p53 deletion were not targeted by macrophages [266].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [266]
In mouse models, inactivating the senescence machinery accelerates tumor development.
“In mouse models, inactivating the senescence machinery results in the acceleration of tumor development, while restoration of senescence in growing tumors causes their regression consistent with the role of senescence in suppressing cancer [266,358].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [266]
In mouse models, restoration of senescence in growing tumors causes their regression.
“In mouse models, inactivating the senescence machinery results in the acceleration of tumor development, while restoration of senescence in growing tumors causes their regression consistent with the role of senescence in suppressing cancer [266,358].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [266]
The secretome of directly affected tumor cells or adjacent senescent stromal fibroblasts can recruit immune cells to contribute to cancer cell removal, reinforcing the tumor suppressive role of senescent tumor cells.
“and can recruit immune cells to contribute to cancer cell removal, reinforcing the tumor suppressive role of senescent tumor cells [263,266].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [266]
Pharmacological p53 reactivation establishes cellular senescence linked to an immunostimulatory SASP that recruits and activates NK cells, TEFF cells, and tumoricidal macrophages.
“Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Lujambio et al., 2013
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Cites
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BackgroundPromotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4
Dapito, D. H., Mencin, A., Gwak, G.-Y., Pradere, J.-P., Jang, M.-K., Mederacke, I., Caviglia, J. M., Khiabanian, H., Adeyemi, A., Bataller, R., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.007 · Cited by 1,346 · see citing works
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“…by the differential expression of gene markers: M1 macrophages express higher levels of inflammatory and antiangiogenic cytokines such as Il1b, whereas M2 macrophages express arginase-1 (Arg1), mannose receptor-1 (Mrc1), and macrophage scavenger receptor 1 (Msr1) (Movahedi et al., 2010).”
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“Although the GFAP promoter is primarily expressed in the adult astroglia, GFAP-Cre; p53 conditional knockout mice show no increased evidence of brain tumors or any other disease (Marino et al., 2000), thus allowing us dissect the role of p53 in HSCs without other confounding phenotypes.”
BackgroundInfluentialTumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
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“…of target genes that mediate its diverse effects (Vousden and Prives, 2009). p53 can limit the propagation of premalignant cells by promoting cell-cycle exit or apoptosis, though p53 has other functions that contribute to its tumor-suppressive action depending on context (Li et al., 2012).”
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“As has been observed in other contexts (Ryan et al., 2000), p53 triggered NF-kB activation as assessed by the nuclear accumulation of the NF-kB subunit p65 (Figures 6B and S6A).”
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Self-citationPten in stromal fibroblasts suppresses mammary epithelial tumours
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“…and Prives, 2009). p53 binds DNA in a sequence-specific manner and controls the expression of target genes that mediate its diverse effects (Vousden and Prives, 2009). p53 can limit the propagation of premalignant cells by promoting cell-cycle exit or apoptosis, though p53 has other…”
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“This carcinogen generates tumors in mice resembling aggressive HCC as assessed histopathologically and by gene expression profiling (Lee et al., 2004).”
BackgroundInterleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice
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“In the context of certain wound-healing responses, SASP limits the extent of tissue damage and facilitates wound resolution (Kong et al., 2012; Krizhanovsky et al., 2008).”
BackgroundFibrosis-dependent mechanisms of hepatocarcinogenesis
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“Following chemical injury to the liver, quiescent HSCs, which are of mesenchymal origin, enter the cell cycle, differentiate, and sustain a chronic inflammatory response accompanied by fibrosis (Zhang and Friedman, 2012).”
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“Accordingly, liver damage in HSC-p53D/D mice was more pronounced, as indicated by decreased serum albumin and increased alanine transaminase levels measured after 13 weeks of treatment (Figure 2A).”
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“Gene set enrichment analysis (GSEA) revealed significant similarities between p53-arrested HSCs and the ‘‘KEGG_p53’’ pathway gene set, as well as a previously identified senescence signature (Figures S4C and S4D and Tables S1A and S1B) (Fridman and Tainsky, 2008).”
BackgroundSelective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis
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BackgroundA Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA Interference
Premsrirut, P. K., Dow, L. E., Kim, S. Y., Camiolo, M., Malone, C. D., Miething, C., Scuoppo, C., Zuber, J., Dickins, R. A., Kogan, S. C., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.012 · Cited by 315 · see citing works
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“Senescent HSCs preferentially secreted Il6, Icam1, and Ifng, whereas proliferating HSCs secreted Il3, Il4, and Il5, among other factors, in agreement with previously reported secretion profiles (Chien et al., 2011; Coppé et al., 2008; Crescenzi et al., 2011).”
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ASC is a Bax adaptor and regulates the p53–Bax mitochondrial apoptosis pathway
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“…we note that several genes upregulated in senescent HSCs (e.g., Eda2r or Pycard) are known NF-kB activators and either established p53 targets (Ohtsuka et al., 2004; Tanikawa et al., 2009) or (e.g., Tnf, Camk2a, Card11, and Ikbkb) harbored consensus p53-binding motifs (Figures S6B and S6C and…”
BackgroundTumor Stroma-Derived TGF-β Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence
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“, 2008) and/or provoke immune surveillance of the senescent cells, leading to their elimination (Kang et al., 2011; Krizhanovsky et al., 2008; Reimann et al., 2010; Xue et al., 2007).”
BackgroundForni, P. E., Scuoppo, C., Imayoshi, I., Taulli, R., Dastrù, W., Sala, V., Betz, U. A. K., Muzzi, P., Martinuzzi, D., Vercelli, A., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2815-06.2006 · Cited by 167 · cited 1× · see citing works
“Though the basis for the male bias remains unclear, we suspect that some form of Cre-mediated damage impacts the proliferation of HSCs as has been seen in some other settings (Forni et al., 2006).”
ResultSun, J. C.-Y., Beilke, J. N., Bezman, N., & Lanier, L. L. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20100479 · Cited by 142 · see citing works
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“Consistent with this view, M2 macrophages accumulate in patients with chronic liver disease (Zimmermann et al., 2011), whereas the accumulation of M1 macrophages has been linked to reduced fibrosis (Hesse et al., 2000).”
BackgroundEvidence for Nonautonomous Effect of <i>p53</i> Tumor Suppressor in Carcinogenesis
Kiaris, H., Chatzistamou, I., Trimis, G., Frangou-Plemmenou, M., Pafiti-Kondi, A., & Kalofoutis, A. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3791 · Cited by 128 · cited 2× · see citing works
“These results are consistent with the observation that MCF7 breast cancer cells produce more tumors when injected subcutaneously into p53 null mice compared to wild-type controls (Kiaris et al., 2005) and are reminiscent of studies supporting a non-cell-autonomous role for Pten in suppressing breast cancer development…”
BackgroundResultNuclear Factor-κB1 (p50) Limits the Inflammatory and Fibrogenic Responses to Chronic Injury
Oakley, F., Mann, J., Nailard, S., Smart, D. E., Mungalsingh, N., Constandinou, C., Ali, S., Wilson, S. J., Millward-Sadler, H., Iredale, J. P., et al. (2005) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)62291-2 · Cited by 123 · see citing works
Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigationsPreprint
Hua, J., Kase, J., Dörr, J. R., Milanovic, M., Lenze, D., Grau, M., Beuster, G., Ji, S., Reimann, M., Lenz, P., et al. (2011) · Genes & Development · doi:10.1101/gad.17620611 · Cited by 99 · cited 6× · see citing works
“These results support the antitumorigenic role of NF-kB in senescent cells (Chien et al., 2011; Jing et al., 2011) and highlight the cooperation between NF-kB and p53 in executing the senescence program.”
BackgroundResultInfluentialCrescenzi, E., Pacifico, F., Lavorgna, A., Palma, R. D., D’Aiuto, E., Palumbo, G. A., Formisano, S., & Leonardi, A. (2011) · Oncogene · doi:10.1038/onc.2011.1 · Cited by 76 · cited 3× · see citing works
“Senescent HSCs preferentially secreted Il6, Icam1, and Ifng, whereas proliferating HSCs secreted Il3, Il4, and Il5, among other factors, in agreement with previously reported secretion profiles (Chien et al., 2011; Coppé et al., 2008; Crescenzi et al., 2011).”
BackgroundFormation of Normal Desmin Intermediate Filaments in Mouse Hepatic Stellate Cells Requires Vimentin
Geerts, A. E., Eliasson, C., Niki, T., Wielant, A., Vaeyens, F., & Pekny, M. (2001) · Hepatology · doi:10.1053/jhep.2001.21045 · Cited by 75 · see citing works
XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway
Tanikawa, C., Furukawa, Y., Yoshida, N., Arakawa, H., Nakamura, Y., & Matsuda, K. (2009) · Oncogene · doi:10.1038/onc.2009.154 · Cited by 67 · cited 2× · see citing works
“, Eda2r or Pycard) are known NF-kB activators and either established p53 targets (Ohtsuka et al., 2004; Tanikawa et al., 2009) or (e.”
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Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994 · see citing works
Self-citationUnderstanding the tumor immune microenvironment (TIME) for effective therapy
Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0014-x · Cited by 6,145 · see citing works
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · see citing works
Mechanisms of hepatic stellate cell activation
Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909 · see citing works
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
“Finally, senescence of hepatic stellate cells may contribute to an altered immune microenvironment that can affect tumorigenesis associated with obesity (Lujambio et al., 2013; Yoshimoto et al., 2013).”
BackgroundKastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Self-citationMechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Mederacke, I., Hsu, C. C., Troeger, J. S., Huebener, P., Mu, X., Dapito, D. H., Pradere, J.-P., & Schwabe, R. F. (2013) · Nature Communications · doi:10.1038/ncomms3823 · Cited by 1,443 · see citing works
Unravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,389 · see citing works
Hepatic stellate cells as key target in liver fibrosis
Higashi, T., Friedman, S. L., & Hoshida, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.007 · Cited by 1,485 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
“The p53-expressing senescent cells release factors that promote macrophage polarization toward antitumor M1 macrophages able to target senescent cells in cultures (215).”
BackgroundMechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
“Eventually, these HSCs enter into senescence, and the SASP contributes to fibrotic scar degradation, clearance of the senescent cells, and restoration of tissue homeostasis (79).”
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177 · see citing works
“2014), and the SASP of senescent hepatic stellate cells (HSCs) participates in fibrotic scar degradation and restores tissue homeostasis in liver fibrosis (Lujambio et al. 2013).”
BackgroundForging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
Senolytic CAR T cells reverse senescence-associated pathologies
Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2403-9 · Cited by 1,098 · see citing works
Self-citationP53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080 · see citing works
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J. (2015) · Science · doi:10.1126/science.aaa5612 · Cited by 982 · see citing works
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
“Macrophages lacking p53 polarize toward M2 and enhance the proliferation of precancerous cells.(136) p53 activation stimulates cellular anti-tumor responses,(137,138) leading to interferon production, and there is a synergistic effect between cancer immunotherapy.”
BackgroundExploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
“Activation or restoration of p53 induces an immunogenic SASP (including, for example, CSF1, CCL2, IL-15, CXCL1, CXCL14 and IGFBP3), which contributes to macrophage-mediated or CD4 + T cell-mediated tumour regression in lymphoma, sarcoma and liver cancer mouse models 71,75,109,173,195,196 .”
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
“Furthermore, senescent activated HSCs are eventually eliminated through senescence surveillance, by either NK cells (Krizhanovsky et al. 2008) or macrophages (Lujambio et al. 2013).”
BackgroundInfluentialThe Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer
Affo, S., Yu, L.-X., & Schwabe, R. F. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100322 · Cited by 757 · see citing works
“As such, activated and proliferating HSCs have been shown to switch monocytes from inflammatory to an immunosuppressive and tumor-promoting M2 phenotype, thus allowing immune evasion by developing tumors (53, 75).”
BackgroundSenescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Hepatic Stellate Cells and Liver Fibrosis
Puche, J. E., Saiman, Y., & Friedman, S. L. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120035 · Cited by 736 · see citing works
Drugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 723 · see citing works
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.
Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., Sansom, O. J., Zender, L., & Keyes, W. M. (2017) · Genes & Development · doi:10.1101/gad.290635.116 · Cited by 650 · see citing works
“However, senescence can also contribute to tumor suppression in a cell-extrinsic manner through senescence-associated secretory phenotype (SASP)-mediated recruitment of immune cells (Kang et al. 2011; Lujambio et al. 2013).”
BackgroundMetabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651 · see citing works
Metabolic control of cell death
Green, D. R., Galluzzi, L., & Kroemer, G. (2014) · Science · doi:10.1126/science.1250256 · Cited by 661 · see citing works
“Moreover, p53 appears to participate in the regulation of organismal homeostasis in a non–cell-autonomous manner, by both immunological (117) and metabolic circuitries (118).”
BackgroundThe liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma
Donné, R., & Lujambio, A. (2022) · Hepatology · doi:10.1002/hep.32740 · Cited by 651 · see citing works
“For example, it has been shown that depending on the context, senescent HSCs can either restrict or promote tumorigenesis through context‐dependent interactions with the immune system.[244,245] In the future, precision medicine will revolutionize HCC therapies, as accumulating evidence suggests that patients who recei…”
BackgroundSelf-citationThe senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601 · see citing works
Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.09.003 · Cited by 609 · see citing works
“Cell 30, 533–547, October 10, 2016 Published by Elsevier Inc. 533 In the liver, cellular senescence has been linked to hepatocellular carcinoma (HCC) suppression (Kang et al., 2011; Lujambio et al., 2013).”
Impaired immune surveillance accelerates accumulation of senescent cells and aging
Ovadya, Y., Landsberger, T., Leins, H., Vadai, E., Gal, H., Biran, A., Yosef, R., Sagiv, A., Agrawal, A., Shapira, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07825-3 · Cited by 578 · see citing works
Self-citationp53 signaling in cancer progression and therapy
Marei, H. E. S., Thani, A. A. A., Afifi, N. M., Hasan, A., Caceci, T., Pozzoli, G., Morrione, A., Giordano, A., & Cenciarelli, C. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02396-8 · Cited by 602 · see citing works
Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape
Wellenstein, M. D., & de Visser, K. E. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.004 · Cited by 581 · see citing works
“…HSCs changed their secretome, induced the polarization of macrophages toward a tumorpromoting phenotype and accelerated inflammation-induced hepatocellular carcinoma (Lujambio et al., 2013), indicating that also stromal cell-intrinsic p53 controls tumorigenesis via modulation of the immune system.”
BackgroundInfluentialMuller, H. L., Merchant, T. E., Warmuth‐Metz, M., Martı́nez-Barberá, J. P., & Puget, S. (2019) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0125-9 · Cited by 526 · see citing works
Senescent cell clearance by the immune system: Emerging therapeutic opportunities
Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2019.04.003 · Cited by 497 · see citing works
Understanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 519 · see citing works
Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
Ruhland, M. K., Loza, A. J., Capietto, A.-H., Luo, X., Knolhoff, B. L., Flanagan, K. C., Belt, B. A., Alspach, E., Leahy, K., Luo, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11762 · Cited by 496 · see citing works
Mutant p53 in cancer: from molecular mechanism to therapeutic modulation
Chen, X., Zhang, T., Su, W., Dou, Z., Zhao, D., Jin, X., Lei, H., Wang, J., Xie, X., Cheng, B., et al. (2022) · Cell Death & Disease · doi:10.1038/s41419-022-05408-1 · Cited by 494 · see citing works
Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246
Cooks, T., Pateras, I. S., Jenkins, L. M. M., Patel, K., Robles, A. I., Morris, J., Forshew, T., Appella, E., Gorgoulis, V. G., & Harris, C. C. (2018) · Nature Communications · doi:10.1038/s41467-018-03224-w · Cited by 483 · see citing works
Origin of myofibroblasts in the fibrotic liver in mice
Iwaisako, K., Jiang, C., Zhang, M., Cong, M., Moore-Morris, T. J., Park, T. J., Liu, X., Xu, J., Wang, P., Paik, Y.-H., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1400062111 · Cited by 535 · see citing works
“By demonstrating that HSCs are the major source of myofibroblasts in hepatotoxic liver injury (CCl4), we confirmed the previous cell fate mapping studies that used GFAP-Cre (56, 57), PDGFRb-Cre (58), and Lrat-Cre (59).”
ResultDifferentiation therapy revisited
de Thé, H. (2018) · Nature reviews. Cancer · doi:10.1038/nrc.2017.103 · Cited by 462 · see citing works
Inside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462 · see citing works
Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets
Yang, Y. M., Kim, S., & Seki, E. (2019) · Seminars in Liver Disease · doi:10.1055/s-0038-1676806 · Cited by 453 · see citing works
Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer
Ruscetti, M., Morris, J. P., Mezzadra, R., Russell, J., Leibold, J., Romesser, P. B., Simon, J., Kulick, A., Ho, Y.-J., Fennell, M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.008 · Cited by 424 · see citing works
“Numerous studies suggest that senescence coordinates tissue remodeling activities associated with wound repair and resolution that are critical for organ homeostasis (Demaria et al., 2014; Krizhanovsky et al., 2008; Lujambio et al., 2013; Mosteiro et al., 2016; Neves et al., 2015).”
Self-citationBRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
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. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0217 · Cited by 415 · see citing works
“We also examined the impact of BRD4 on the ability of senescent cells to modulate immune cell function and facilitate senescent cell targeting (26, 33).”
InfluentialSelf-citationSUMO and the robustness of cancer
Seeler, J.-S., & Dejean, A. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.143 · Cited by 425 · see citing works
Mechanisms of liver fibrosis and its role in liver cancer
Dhar, D., Baglieri, J., Kisseleva, T., & Brenner, D. A. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370219898141 · Cited by 440 · see citing works
“HSCs SASP can skew macrophage polarization towards a tumorinhibiting M1-state, and inhibiting the HSCs SASP by p53 deletion results in M2 macrophage polarization and HCC promotion.(163) HSC activation can also directly influence HCC development by secreting critical cytokines and chemokines such as HGF, TGF-b, PDGF, I…”
BackgroundQuantitative identification of senescent cells in aging and disease
Biran, A., Zada, L., Abou Karam, P., Vadai, E., Roitman, L., Ovadya, Y., Porat, Z., & Krizhanovsky, V. (2017) · Aging Cell · doi:10.1111/acel.12592 · Cited by 402 · see citing works
“They interact with the immune system to regulate their presence and modify the microenvironment (Xue et al., 2007; Krizhanovsky et al., 2008; Lujambio et al., 2013; Biran et al., 2015; Sagiv et al., 2016).”
BackgroundSelf-citationIannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130783 · Cited by 414 · see citing works
“…of p53 with doxycycline resulted in the arrest of tumor growth and the gradual disappearance of the senescent tumors may play a role in tumor surveillance as well as in resolution of fibrotic injury to tissues (Xue et al., 2007; Krizhanovsky et al., 2008; Kang et al., 2011; Lujambio et al., 2013).”
Self-citationCai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 436 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
“Additionally, the secretome of directly affected tumor cells or adjacent senescent stromal fibroblasts can induce paracrine senescence of nearby tumor cells [270] and can recruit immune cells to contribute to cancer cell removal, reinforcing the tumor suppressive role of senescent tumor cells [263,266].”
BackgroundImmunological impact of cell death signaling driven by radiation on the tumor microenvironment
Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I., & Galluzzi, L. (2020) · Nature Immunology · doi:10.1038/s41590-019-0561-4 · Cited by 385 · see citing works
Recurrent turnover of senescent cells during regeneration of a complex structure
Yun, M. H., Davaapil, H., & Brockes, J. P. (2015) · eLife · doi:10.7554/elife.05505 · Cited by 385 · see citing works
“…to be characteristic of regeneration, as no significant induction of senescence takes place during normal limb development (Figure 2E, Figure 2—figure supplement 2), in contrast to previous findings in amniotic limb development (Banito and Lowe, 2013; Munoz-Espin et al., 2013; Storer et al., 2013).”
ResultLong noncoding RNAs: Novel insights into hepatocelluar carcinoma
He, Y., Meng, X., Huang, C., Wu, B., Zhang, L., Lv, X., & Li, J. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.10.021 · Cited by 385 · see citing works
“As the p53 gene is an important tumor suppressor gene [40–42].”
BackgroundMacrophage Plasticity and Polarization in Liver Homeostasis and Pathology
Sica, A., Invernizzi, P., & Mantovani, A. (2014) · Hepatology · doi:10.1002/hep.26754 · Cited by 422 · see citing works
“By releasing factors that stimulate M2 macrophage polarization, p53-deficient stellate cells create a tumorpromoting environment.(56) Phagocytosis of dying necrotic cells and debris triggers production of TGF-b by KCs and recruited Fig.”
Aydin, M. M., & Akçalı, K. C. (2018) · The Turkish Journal of Gastroenterology · doi:10.5152/tjg.2018.17330 · Cited by 388 · see citing works
p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R. Z., Nevo, Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4054 · Cited by 351 · see citing works
Takahashi, A., Loo, T. M., Okada, R., Kamachi, F., Watanabe, Y., Wakita, M., Watanabe, S., Kawamoto, S., Miyata, K., Barber, G. N., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03555-8 · Cited by 350 · see citing works
Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis
Filliol, A., Saito, Y., Nair, A., Dapito, D. H., Yu, L.-X., Ravichandra, A., Bhattacharjee, S., Affo, S., Fujiwara, N., Su, H., et al. (2022) · Nature · doi:10.1038/s41586-022-05289-6 · Cited by 349 · see citing works
Senescent cells and osteoarthritis: a painful connection
Jeon, O. H., David, N. E., Campisi, J., & Elisseeff, J. H. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95147 · Cited by 354 · see citing works
“Senescent stellate cells secrete factors that favor macrophage polarization toward a proinflammatory M1 state, which also promotes SnC clearance (111).”
The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy
Scherz-Shouval, R., Santagata, S., Mendillo, M. L., Sholl, L. M., Ben-Aharon, I., Beck, A. H., Dias-Santagata, D., Koeva, M., Stemmer, S. M., Whitesell, L., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.045 · Cited by 386 · see citing works
“In mouse models, tumor suppressors such as p53 and PTEN can act in the stroma to limit tumor growth (Lujambio et al., 2013; Moskovits et al., 2006; Trimboli et al., 2009).”
Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Prasanna, P. G. S., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., Xi, D., Zheng, G., van Deursen, J., Goronzy, J. J., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab064 · Cited by 351 · see citing works
“Similarly, activation of p53 in hepatic stellate cells due to senescence induced by CCl4 and the carcinogen diethyl-nitrosamine in mice reduced fibrosis and cirrhosis, besides inhibiting liver epithelial tumorigenesis because of immune clearance of SnCs (60).”
BackgroundSelf-citationRole of immune cells in the removal of deleterious senescent cells
Kale, A., Sharma, A., Stolzing, A., Desprez, P.-Y., & Campisi, J. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00187-9 · Cited by 351 · see citing works
“factors, which shift macrophages to the M2 state [59].”
BackgroundCellular senescence in renal ageing and disease
Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J., & van Deursen, J. M. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.183 · Cited by 345 · see citing works
Mutant p53 Suppresses Innate Immune Signaling to Promote Tumorigenesis
Ghosh, M., Saha, S., Bettke, J. A., Nagar, R., Parrales, A., Iwakuma, T., van der Velden, A. W. M., & Martinez, L. A. (2020) · Cancer Cell · doi:10.1016/j.ccell.2021.01.003 · Cited by 344 · see citing works
p53, cancer and the immune response
Blagih, J., Buck, M. D., & Vousden, K. H. (2020) · Journal of Cell Science · doi:10.1242/jcs.237453 · Cited by 333 · see citing works
“This response attracts NK and myeloid cells that can function to remove damaged hepatocytes and so limit fibrosis, cirrhosis and HCC development (Krizhanovsky et al., 2008; Lujambio et al., 2013) (Fig.”
BackgroundEmerging roles of p53 and other tumour-suppressor genes in immune regulation
Muñoz‐Fontela, C., Mandinova, A., Aaronson, S. A., & Lee, S. W. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.99 · Cited by 342 · see citing works
Liedtke, C., Luedde, T., Sauerbruch, T., Scholten, D., Streetz, K. L., Tacke, F., Tolba, R. H., Trautwein, C., Trebicka, J., & Weiskirchen, R. (2013) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-6-19 · Cited by 336 · see citing works
The post-translational modification, SUMOylation, and cancer (Review)
Han, Z., Feng, Y.-H., Gu, B.-H., Li, Y., & Chen, H. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4280 · Cited by 337 · see citing works
“…chemokines, growth factors and matrix remodeling factors or matrix metalloproteinases, which alter the local tissue environment and contributes to chronic inflammation and cancer (201). p53 promotes cellular senescence, as well as programmed cell death (apoptosis) as a tumor suppressor (202).”
Tumor-Suppressor Functions of the TP53 PathwayPreprint
Aubrey, B. J., Strasser, A., & Kelly, G. L. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026062 · Cited by 331 · see citing works
“For example, in a mouse model of hepatocellular carcinoma, TP53 was shown to influence the microenvironment and immune response via a non-tumor-cell-autonomous mechanism, which impacted the rate of tumor expansion and aggressiveness (Lujambio et al. 2013).”
BackgroundBorghesan, M., Fafián-Labora, J., Eleftheriadou, O., Carpintero-Fernández, P., Paez-Ribes, M., Vizcay-Barrena, G., Swisa, A., Kolodkin-Gal, D., Ximénez-Embún, P., Lowe, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.095 · Cited by 315 · see citing works
“, 2017); and (3) ex vivo mouse hepatic stellate cells (mHSCs) derived from an adult mouse harboring a doxycycline (Dox)inducible construct to express shp53 (Krizhanovsky et al., 2008; Lujambio et al., 2013) (Figure S1L).”
BackgroundResultInhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth
Baell, J. B., Leaver, D. J., Hermans, S. J., Kelly, G. L., Brennan, M. S., Downer, N. L., Nguyen, N. H., Wichmann, J., McRae, H. M., Yang, Y., et al. (2018) · Nature · doi:10.1038/s41586-018-0387-5 · Cited by 321 · see citing works
p53 and Tumor Suppression: It Takes a Network
Boutelle, A. M., & Attardi, L. D. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.12.011 · Cited by 322 · see citing works
Watanabe, S., Kawamoto, S., Ohtani, N., & Hara, E. (2017) · Cancer Science · doi:10.1111/cas.13184 · Cited by 321 · see citing works
Andoniadou, C. L., Matsushima, D., Mousavy-Gharavy, S. N., Signore, M., Mackintosh, A. I., Schaeffer, M., Gaston‐Massuet, C., Mollard, P., Jacques, T. S., Tissier, P. L., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.07.004 · Cited by 314 · see citing works
“Recently, a non-cell-autonomous effect of p53 was shown in a model of hepatocellular carcinoma, where p53-ablated hepatic stellate cells were able to induce tumors in a paracrine fashion (Lujambio et al., 2013).”
BackgroundUHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma
Mudbhary, R., Hoshida, Y., Chernyavskaya, Y., Jacob, V., Villanueva, A., Fiel, M. I., Chen, X., Kojima, K., Thung, S. N., Bronson, R. T., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.003 · Cited by 310 · see citing works
“, 2007) and in hepatic stellate cells (Table S6; Figure S6C; Lujambio et al., 2013).”
BackgroundMethodInfluentialRecent advancement of molecular mechanisms of liver fibrosis
Seki, E., & Brenner, D. A. (2015) · Journal of Hepato-Biliary-Pancreatic Sciences · doi:10.1002/jhbp.245 · Cited by 299 · see citing works
“the polarization of liver macrophages to M1-state through their senescence-associated secretory phonotype (SASP), resulting in inhibiting the development of hepatocellular carcinoma (HCC) [48].”
BackgroundInfluentialRole of nonresolving inflammation in hepatocellular carcinoma development and progression
Yu, L., Yan, L., & Wang, H. (2018) · npj Precision Oncology · doi:10.1038/s41698-018-0048-z · Cited by 302 · see citing works
“A recent report showed that deletion of p53 in hepatic stellate cells led to the macrophage M2 polarization thus avoided immune elimination and resulted in accelerated HCC development in a DEN-induced HCC model.(100) Moreover, liver macrophages in the Fig.”
BackgroundCellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
Ohtani, N. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00197-8 · Cited by 306 · see citing works
“SASP factors can also act in a paracrine manner, inducing senescence of surrounding cells, and this is termed as paracrine senescence [10].”
BackgroundAcute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure
de Thé, H., Pandolfi, P. P., & Chen, Z. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.10.002 · Cited by 295 · see citing works
“In mouse models, senescence seems implicated in APL clearance, and the immune system is critically important to eliminate senescent cells (Ablain et al., 2014; Korf et al., 2014; Lujambio et al., 2013; Nardella et al., 2011).”
BackgroundCuollo, L., Antonangeli, F., Santoni, A., & Soriani, A. (2020) · Biology · doi:10.3390/biology9120485 · Cited by 291 · see citing works
Genetic and non-genetic clonal diversity in cancer evolution
Black, J. R., & McGranahan, N. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00336-2 · Cited by 287 · see citing works
DNA damage response and metabolic disease
Shimizu, I., Yoshida, Y., Suda, M., & Minamino, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.008 · Cited by 286 · see citing works
The p53 network: cellular and systemic DNA damage responses in cancer and aging
Vaddavalli, P. L., & Schumacher, B. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.02.010 · Cited by 295 · see citing works
Cell fusion induced by ERVWE1 or measles virus causes cellular senescence
Chuprin, A., Gal, H., Biron-Shental, T., Biran, A., Amiel, A., Rozenblatt, S., & Krizhanovsky, V. (2013) · Genes & Development · doi:10.1101/gad.227512.113 · Cited by 262 · see citing works
“SASP components were shown to either inhibit or promote cancer progression in a cell-nonautonomous manner in different settings (Canino et al. 2012; Lujambio et al. 2013).”
BackgroundSelf-citationBird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261 · see citing works
“SASP may also modulate fibrosis and regeneration in response to acute tissue injury (11, 16, 17).”
Xiao, Y., Chen, J., Zhou, H., Zeng, X., Ruan, Z., Pu, Z., Jiang, X., Matsui, A., Zhu, L., Amoozgar, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28279-8 · Cited by 267 · see citing works
Macrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262 · see citing works
“SASP factors secreted from hepatic stellate cells shift macrophage polarization from M2 toward M1.(75) Accordingly, it is likely that exogenous changes in the microenvironment (e.”
BackgroundInfluentialPhysiological and pathological consequences of cellular senescence
Burton, D. G. A., & Krizhanovsky, V. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1691-3 · Cited by 253 · see citing works
“A recent study has shown that senescent HSCs can be eliminated by another component of the innate immune system, the M1-like macrophages during liver damage and tumorigenesis in the liver [89].”
BackgroundSelf-citationThe wound healing, chronic fibrosis, and cancer progression triad
Rybinski, B., Franco‐Barraza, J., & Cukierman, E. (2014) · Physiological Genomics · doi:10.1152/physiolgenomics.00158.2013 · Cited by 255 · see citing works
Malaquin, N., Martinez, A., & Rodier, F. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.05.010 · Cited by 247 · see citing works
“, 2016)} and selective immune clearance have emerged as promising strategies to selectively eliminate senescent cells (Kang et al., 2011; Lujambio et al., 2013; Xue et al., 2007).”
Senescent cells: SASPected drivers of age-related pathologies
Ovadya, Y., & Krizhanovsky, V. (2014) · Biogerontology · doi:10.1007/s10522-014-9529-9 · Cited by 232 · see citing works
“Senescent hepatic stellate cells (HSCs) release SASP factors such as IFN-c and IL-6 that skew macrophage toward the M1 state during liver disease (Lujambio et al. 2013).”
BackgroundSelf-citationDurán, Á., Hernandez, E. D., Reina‐Campos, M., Castilla, E. A., Subramaniam, S., Raghunandan, S., Roberts, L. R., Kisseleva, T., Karin, M., Díaz-Meco, M. T., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.09.004 · Cited by 240 · see citing works
“…in GFAP-Cre mice was reported to result in three outcomes: (1) recombination only in HSCs (Kisseleva and Brenner, 2008; Krizhanovsky et al., 2008; Lujambio et al., 2013); (2) recombination only in cholangiocytes (Mederacke et al., 2013); and (3) recombination in both HSCs and cholangiocytes…”
Influentialp53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer
Tschaharganeh, D. F., Xue, W., Calvisi, D. F., Evert, M., Michurina, T. V., Dow, L. E., Banito, A., Katz, S. F., Kastenhuber, E. R., Weissmueller, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.051 · Cited by 227 · see citing works
Self-citationThe current paradigm and challenges ahead for the dormancy of disseminated tumor cells
Risson, E., Nobre, A. R., Maguer‐Satta, V., & Aguirre‐Ghiso, J. A. (2020) · Nature Cancer · doi:10.1038/s43018-020-0088-5 · Cited by 235 · see citing works
- Authors
- Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., Zhao, Z., Thapar, V., Joyce, J. A., Krizhanovsky, V., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Krizhanovsky, Valery
- Lowe, Scott W.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 153
- Issue
- 2
- Pages
- 449-460
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3702034
- OpenAlex
- W2104397341
- Cited by
- 766
- References
- 48
- Citations by year
- 2026: 35 · 2025: 67 · 2024: 61 · 2023: 52 · 2022: 66 · 2021: 74 · 2020: 70 · 2019: 51 · 2018: 62 · 2017: 57 · 2016: 49 · 2015: 47 · 2014: 46 · 2013: 28
- FWCI
- 39.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- Cold Spring Harbor Laboratory
- Deutsche Forschungsgemeinschaft
- Weizmann Institute of Science
- Israel Science Foundation
- National Institute on Aging (R56AG016379, AG-16379, R01AG016379)
- National Cancer Institute (P01CA087497, U54CA148967, P01CA013106, P30CA008748)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- p53, cellular senescence, hepatic stellate cells, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, macrophage polarization, M1/M2 macrophages, tumor microenvironment, chronic liver injury, premalignant cells, secreted factors
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Fibrosis, Humans, Inflammation, Kupffer Cells, Liver, Liver Neoplasms, Macrophages, Tumor Suppressor Protein p53, NF-kappa B, Cellular Senescence, Mice, Hepatic Stellate Cells, Cellular Microenvironment
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