The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
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
“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]
The cited source says what the claim attributes to it.
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
The cited source says what the claim attributes to it.
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
“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]
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
Cites
Macrophage Diversity Enhances Tumor Progression and Metastasis
Qian, B., & Pollard, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.03.014 · Cited by 5,338 · cited 2×
“The most notable changes involved factors known to influence the differentiation and activity of macrophages (e.g., Il6, Ifng, and Il4 [Qian and Pollard, 2010]), a cell type known to modulate liver fibrosis (Duffield Cell 153, 449–460, April 11, 2013 ª2013 Elsevier Inc. 453 Figure 5. p53 Signaling…”
BackgroundBataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · cited 2×
“Indeed, the senescent state triggered by p53 caused a significant increase in the secretion of factors known to promote M1 polarization, which is characterized by Il1b expression and an increased propensity for cell killing and phagocytosis (Biswas and Mantovani, 2010).”
BackgroundBlinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · cited 2×
“…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…”
BackgroundSenescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Self-citationOncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027 · cited 16×
“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).”
BackgroundMethodResultInfluentialSelf-citationGender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production
Naugler, W. E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A. M., & Karin, M. (2007) · Science · doi:10.1126/science.1140485 · Cited by 1,955
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., et al. (2011) · Nature · doi:10.1038/nature10334 · Cited by 1,870
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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
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
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366
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
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
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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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