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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 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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
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In the citing paper
“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
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In the citing paper
“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]
In the citing paper
“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 the citing paper
“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
In the citing paper
“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 the citing paper
“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 the citing paper
“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 the citing paper
“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 the citing paper
“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]
In the citing paper
“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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Citations
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Zellmer, V. R., & Zhang, S. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-69 · Cited by 91
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“Interestingly, p53-deficient HSCs bypass senescence and secrete factors that stimulate macrophages into a tumor-promoting M2 state, suggesting a nonautonomous tumor suppressor activity for p53 (Lujambio et al. 2013).”
BackgroundNon-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
Saleh, T., Tyutynuk-Massey, L., Cudjoe, E. K., Idowu, M. O., Landry, J. W., & Gewirtz, D. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00164 · Cited by 85
“The role of p53 in SASP regulation is further shown in senescent hepatic stellate cells implicated in hepatic cirrhosis where p53 ablation attenuates the inflammatory drive mediated by SASP (19).”
BackgroundYashaswini, C. N., Qin, T., Bhattacharya, D., Amor, C., Lowe, S. W., Lujambio, A., Wang, S., & Friedman, S. L. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.03.014 · Cited by 90
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“Further, Lujambio and colleagues showed that Tp53-deficient hepatic stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2 state leading to increased liver fibrosis and accelerated transformation of adjacent hepatocytes (Lujambio et al., 2013).”
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“TP53 plays a fundamental role in inducing SASP and senescence (52), and the TP53 target p21 (together with interleukin-1, IL-1) is among the top genes up-regulated after induction of chromosome missegregation and aneuploidy in TP53 wild-type cells (53).”
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“During chronic liver damage, ablation of a p53-dependent induction of senescence in hepatic stellate cells can promote transformation and tumour formation by adjacent epithelial cells, confirming non-cell autonomous tumour suppressor functions of p53 [113].”
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“The spread of cancer cells involves the complex relation between cancer cells and host cells, which are defined by desmoplastic reactions, tumor stroma, or TME interactions.60-63 Cancer cells are surrounded by tumor stroma, which is constituted of immune cells, capillaries, basement membrane, activated fibroblasts, an…”
BackgroundCell senescence in neuropathology: A focus on neurodegeneration and tumours
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Stress-induced β cell early senescence confers protection against type 1 diabetes
Lee, H., Sahin, G. S., Chen, C.-W., Sonthalia, S., Cañas, S. M., Oktay, H. Z., Duckworth, A. T., Brawerman, G. M., Thompson, P. J., Hatzoglou, M., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.014 · Cited by 66
Kamaraj, B., & Bogaerts, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134638 · Cited by 62
Neelakantan, D., Drasin, D. J., & Ford, H. L. (2014) · Cell Adhesion & Migration · doi:10.4161/19336918.2014.972761 · Cited by 64
“For instance, p53 expression in hepatic stellate cells has been shown to non-cell autonomously curb initiation of hepatocellular carcinoma by promoting an anti-tumor microenvironment via secretion of senescence promoting factors in the murine liver.(75) Fibroblasts in the tumor microenvironment have also been shown to…”
BackgroundWogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression
Yang, D., Guo, Q., Liang, Y., Zhao, Y., Tian, X., Ye, Y., Tian, J., Wu, T., & Lu, N. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02842-y · Cited by 63
Senescent stromal cells: roles in the tumor microenvironment
Gabai, Y., Assouline, B., & Ben‐Porath, I. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.09.002 · Cited by 67
The Origin and Fate of Liver Myofibroblasts
Kim, H. Y., Sakane, S., Eguileor, A., Carvalho Gontijo Weber, R., Lee, W., Liu, X., Lam, K., Ishizuka, K., Rosenthal, S. B., Diggle, K., et al. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.09.008 · Cited by 63
p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine
Krstić, J., Galhuber, M., Schulz, T. J., Schupp, M., & Prokesch, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030921 · Cited by 65
“Importantly, p53-expressing HSCs were shown to stimulate the tumor-inhibiting M1 phenotype of macrophages in HCC, while p53-depleted HSCs stimulated differentiation of macrophages into the M2 phenotype [118].”
BackgroundInfluentialHe, X., Xiang, C., Zhang, C.-X., Xie, Y., Chen, L., Zhang, G.-X., Lu, Y., & Liu, G. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.045 · Cited by 64
Chan, Y.-T., Wang, N., Tan, H. Y., Li, S., & Feng, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00548 · Cited by 63
“Senescence is mainly mediated by the p53dependent pathway, and the attenuation of this program in HSCs enhances liver fibrosis and exacerbates the chances of developing into HCCs (Lujambio et al., 2013).”
BackgroundSenescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword
Battram, A. M., Bachiller, M., & Martín-Antonio, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124346 · Cited by 66
Cellular senescence and protein degradation
Deschênes‐Simard, X., Lessard, F., Gaumont‐Leclerc, M., Bardeesy, N. M., & Ferbeyre, G. (2014) · Cell Cycle · doi:10.4161/cc.29335 · Cited by 66
Senescence and cancer: An evolving inflammatory paradox
Ruhland, M. K., Coussens, L. M., & Stewart, S. A. (2015) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2015.10.001 · Cited by 62
“A DMBA (7,12-dimethylbenz(a)anthracene)-initiated model of HCC demonstrated that livers of obese mice were predisposed to tumor development via DCA (deoxycholic acid)induced senescent hepatic stellate cells.”
InfluentialLuo, X., Jiang, X., Li, J., Bai, Y., Li, Z., Wei, P., Sun, S., Liang, Y., Han, S., Li, X., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1670-6 · Cited by 60
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments
de Bakker, T., Journé, F., Descamps, G., Saussez, S., Dragan, T., Ghanem, G., Krayem, M., & Gestel, D. V. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.799993 · Cited by 64
“A first model of chronic liver damage has initially demonstrated that proliferating stellate cells deficient for p53 were able to stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells (99) Since then, many studies focused on the clinical and prognosti…”
Filliol, A. A., & Schwabe, R. F. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1685539 · Cited by 60
Roles of tumor suppressors in regulating tumor-associated inflammation
Yang, L., & Karin, M. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.131 · Cited by 59
Senescence under appraisal: hopes and challenges revisited
Davan-Wetton, C. S. A., Pessolano, E., Perretti, M., & Montero‐Melendez, T. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03746-x · Cited by 61
“Senescent stellate cells were shown to induce macrophage class-switch towards M1 phenotype favouring their clearance, while proliferating cells induced an M2 phenotype creating a tumour-promoting environment [89].”
Backgroundp53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions
Fujita, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236023 · Cited by 59
Cerchietti, L. C. A. (2024) · Blood · doi:10.1182/blood.2023021002 · Cited by 62
A Crucial Role for CDC42 in Senescence-Associated Inflammation and Atherosclerosis
Ito, T. K., Yokoyama, M., Yoshida, Y., Nojima, A., Kassai, H., Oishi, K., Okada, S., Kinoshita, D., Kobayashi, Y., Fruttiger, M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102186 · Cited by 58
“cancer by leading to the elimination of cells with oncogenes, which have the potential to become malignant [9,10].”
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Mutant p53 oncogenicity: dominant-negative or gain-of-function?
Stein, Y., Aloni-Grinstein, R., & Rotter, V. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa117 · Cited by 62
Molecular mechanisms of hepatic apoptosis regulated by nuclear factors
Wang, K. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.11.038 · Cited by 56
Jin, H., Jia, Y., Yao, Z., Huang, J., Hao, M., Yao, S., Lian, N., Zhang, F., Zhang, C., Chen, X., et al. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.02.006 · Cited by 60
“Recently, although evidence has suggested that cell proliferation inhibition and apoptosis induction were potential strategies to block the activation of HSCs, senescence of HSC limited the development of fibrosis resulting from hepatic injury [12-14].”
BackgroundZhang, G., Yuan, J., Qian, G., Gu, C.-X., Wei, K., Mo, D., Qin, J., Peng, Y., Zhou, Z., Pan, C., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01769 · Cited by 56
Regulation and function of p53: A perspective from Drosophila studies
Ingaramo, M., Sánchez, J., & Dekanty, A. (2018) · Mechanisms of Development · doi:10.1016/j.mod.2018.05.007 · Cited by 56
The metabolic axis of macrophage and immune cell polarization
Hobson-Gutierrez, S., & Carmona‐Fontaine, C. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.034462 · Cited by 57
“As with TAMs, M2-like macrophages favor tumor growth (see, for example, Hughes et al., 2015; Lujambio et al., 2013; Murray, 2018).”
Cheng, K.-C., Wang, C., Chang, Y., Hung, T., Lai, C.-J., Kuo, C.-W., & Huang, H. (2019) · Journal of Food and Drug Analysis · doi:10.1016/j.jfda.2019.06.002 · Cited by 56
“In addition, loss of p53 promotes the transformation of contiguous epithelial cells into HCC [30].”
Translational Control during Cellular Senescence
Payea, M. J., Anerillas, C., Tharakan, R., & Gorospe, M. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00512-20 · Cited by 56
p53 in Bronchial Club Cells Facilitates Chronic Lung Inflammation by Promoting Senescence
Sagiv, A., Bar-Shai, A., Levi, N., Hatzav, M., Zada, L., Ovadya, Y., Roitman, L., Manella, G., Regev, O., Majewska, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.009 · Cited by 55
Self-citationThe role of matrix stiffness in cancer stromal cell fate and targeting therapeutic strategies
Wei, J., Yao, J., Yan, M., Xie, Y., Liu, P., Mao, Y., & Li, X. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.08.005 · Cited by 57
Immunosurveillance as a regulator of tissue homeostasis
Senovilla, L., Galluzzi, L., Zitvogel, L., & Kroemer, G. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.06.005 · Cited by 57
Mutant p53 in cell-cell interactionsPreprint
Pilley, S. E., Rodríguez, T. A., & Vousden, K. H. (2021) · Genes & Development · doi:10.1101/gad.347542.120 · Cited by 54
“…tissue by suppressing the expression of SDF-1/CXCL12, a chemokine that increases cell invasiveness (Moskovits et al. 2006) and the release of factors from p53-expressing hepatic stellate cells that promote macrophage polarization toward the tumor-suppressive M1 type (Lujambio et al. 2013).”
BackgroundXiong, J., Dong, L., Lv, Q., Yin, Y., Zhao, J., Ke, Y., Wang, S., Zhang, W., & Wu, M. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1772 · Cited by 58
“95 Furthermore, in hepatic stellate cells, p53-induced senescence triggers the production of SASP factors including IL-6, ICAM1 and IFN-𝛾 , which promote macrophage polarisation shifting from an immune-suppressive M2 state to an immune-stimulatory M1 state.”
BackgroundImmune Surveillance of Unhealthy Cells by Natural Killer CellsPreprint
Iannello, A., & Raulet, D. H. (2013) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2013.78.020255 · Cited by 60
“Lujambio et al. (2013) recently reported that p53-restored senescent stellate cells secreted IL-1a, IL-6, and IFN-g, skewing macrophage polarization toward a tumor-inhibiting M1-state, whereas stellate cells lacking p53 secreted IL-3, IL-4, and IL-5, stimulating polarization of macrophages into a…”
Circumventing senescence is associated with stem cell properties and metformin sensitivity
Deschênes‐Simard, X., Parisotto, M., Rowell, M., Le Calvé, B., Igelmann, S., Moineau‐Vallée, K., Saint‐Germain, E., Kalegari, P., Bourdeau, V., Kottakis, F., et al. (2019) · Aging Cell · doi:10.1111/acel.12889 · Cited by 45
“In the liver, the SASP also plays a role in stimulation of antitumor immune responses (Iannello, Thompson, Ardolino, Lowe, & Raulet, 2013; Lujambio et al., 2013).”
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Therapy-induced senescence as a component of tumor biology: Evidence from clinical cancer
Saleh, T., Bloukh, S., Hasan, M., & Shboul, S. A. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188994 · Cited by 55
Cellular senescence in the tumor microenvironment and context‐specific cancer treatment strategies
Yasuda, T., Baba, H., & Ishimoto, T. (2021) · FEBS Journal · doi:10.1111/febs.16231 · Cited by 53
Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain
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The role of lipid-based signalling in wound healing and senescence
Pils, V., Terlecki‐Ζaniewicz, L., Schosserer, M., Grillari, J., & Lämmermann, I. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111527 · Cited by 56
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Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy
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“…of cytokines, including interleukin 8 (IL-8), by cells undergoing senescence enables recruitment of innate immune cells, such as macrophages (Lujambio et al, 2013) and natural killers (NK) cells, which can shrink and eliminate tumors (Xue et al, 2007; Serrano, 2011; Iannello et al, 2013;…”
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“Moreover, p53 driven senescence in chronically damaged livers could activate macrophages that contributed to non-cell autonomous tumor suppression [39].”
Background
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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