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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
“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
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BackgroundRising from the ashes: cellular senescence in regeneration
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“Tumor-associated macrophages (TAMs) are the core of the immune-suppressive cell and cytokine network 28 , and SASP can induce their polarization into either M1-like or M2-like phenotypes 29 .”
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“…in the presence of chronic liver damage, ablation of a p53-dependent senescence program in hepatic stellate cells enhanced the transformation of adjacent epithelial cells into hepatocellular carcinoma by skewing macrophage polarization towards a tumor-promoting M2-state (Lujambio et al., 2013).”
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“Deletion of p53 in hepatic stellate cells induces the formation of epithelial tumors that are primarily wild type for p53 (Lujambio et al., 2013).”
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Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer
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“For examples, Lujambio and colleagues report that NF-kB mediates p53-dependent SASP and they cooperate to induce SASP (50), whereas others reveal that p53 can inhibit NF-kB activity and inflammation (51).”
Backgroundp53 in liver pathologies—taking the good with the bad
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“Accumulating evidence suggests that immune cells, including NK cells, T cells, macrophages and neutrophils, can clear premalignant cells and senescent tumor cells (18-20,35,36).”
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“This reprogramming enables large-scale MMP12/ ADAMTS5 secretion for collagen degradation while recruiting TIMP1 + macrophages via CCL17 signaling to resolve fibrotic matrices [132, 133].”
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p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino
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“Exacerbation of liver fibrotic changes, as well as induction of neighboring epithelial cells transformed intoHCC, occurs when the aging response in hepatic stellate cells, which relies on p53, is eliminated (Lujambio et al., 2013).”
BackgroundHoare, M., & Narita, M. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-89512-3_15 · Cited by 23
Plasticity, heterogeneity, and multifunctionality of hepatic stellate cells in liver pathophysiology
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The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence
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“Lujambio et al found that senescent hepatic stellate cells could stimulate the recruitment and M1 polarization of macrophages to suppress tumorigenesis and to form an antitumor microenvironment.(69) On the other hand, contrary to the originally proposed tumor suppressor function of senescent cells, SASPs secreted by s…”
BackgroundmiRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer
Mühlberg, L., Kühnemuth, B., Costello, E., Shaw, V. E., Sipos, B., Huber, M., Griesmann, H., Krug, S., Schober, M., Gress, T. M., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1160181 · Cited by 22
“showed that deficiency of p53 can favor M2polarization in a non-tumor cell autonomous fashion.(29) However, we did not observe significant differences in M1- or M2marker expression between KC- and KPC-mice with PanIN lesions indicating that morphologically similar precursor lesions exert similar paracrine effects on i…”
ResultZahraeifard, S., Xiao, Z., So, J. Y., Ahad, A., Montoya, S., Park, W. Y., Sornapudi, T., Andohkow, T., Read, A., Kedei, N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50262-8 · Cited by 24
The context-dependent effect of cellular senescence: From embryogenesis and wound healing to aging
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Novel p53 target genes secreted by the liver are involved in non-cell-autonomous regulation
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“but also its surroundings, by modulating the expression of genes that encode for secreted factors.(6,7) Recently, it was”
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New and Old Key Players in Liver Cancer
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“This phenomenon is increasingly described in several other cancer model systems and extends the traditional understanding of cancer initiation as a cell autonomous process (28, 31).”
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“For example, p53 has been shown to promote classical (and antitumoral) polarization of tumor-associated macrophages in a non-cell-autonomous manner.(71) In addition, p53 directly induces the expression of miR-34 that impairs the expression of PD-L1 and may thus license malignant cells with intact p53 for cytotoxic T-c…”
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“Moreover, innate immune signals create microenvironments hostile for tumorigenicity in conjunction with tumor suppressor systems including oncogene-induced senescence and DNA damage signals.(4,5) These findings imply that molecular links exist between intrinsic and immune-mediated surveillance in controlling antitumor…”
Backgroundp53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance
Souza, L. C. D. M. E., Faletti, A., Veríssimo, C. P., Stelling, M. P., & Borges, H. L. (2022) · Membranes · doi:10.3390/membranes12020202 · Cited by 20
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“79 In mouse models of myeloid lineage-specific p53 activation, p53 activation inhibits M2 macrophage polarization and c-Myc down-regulation.”
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Stromal-MDM2 Promotes Lung Cancer Cell Invasion through Tumor–Host Feedback Signaling
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“There is evidence that senescent cells under senescence surveillance are eliminated by macrophages (45) or NK cell-mediated induction of granule exocytosis (46, 47).”
BackgroundReshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy
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“12,13,30 Although Lujambio et al showed a protective role of p53-induced HSC senescence, 12 Yoshimoto et al reported that HSC senescence rather promotes liver cancer.”
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“Recent reports confirm such a role of p53 in TAM biology.(80,81)”
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“It was shown that the formation of HCC did not directly evolve from p53-depleted HSCs, rather its deletion in these cells created a niche for hepatocytes malignant transformation (36).”
BackgroundProtein of a thousand faces: The tumor-suppressive and oncogenic responses of p53
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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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