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Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression
Open accessAbstract
Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2+ myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2+ myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC.
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“Moreover, a senescenceassociated gene signature was identified in the peritumoural area of hepatocellular carcinomas both in mice and humans, with the presence of this signature in the latter correlating with poor overall survival 90 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [90]
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“By contrast, during cancer development associated with accumulation of senescent cells, SASP can recruit immature myeloid cells to promote tumorigenesis in a paracrine manner160,161.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [161]
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“Further, the SASP can recruit immature immune-suppressive myeloid cells to prostate and liver tumors (Di Mitri et al., 2014; Eggert et al., 2016) and stimulate tumorigenesis by driving angiogenesis and metastasis (Coppe ´ et al., 2010).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Eggert et al., 2016
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“In some instances, the SASP can also have immunosuppressive functions (Di Mitri et al. 2014; Eggert et al. 2016).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Eggert et al. 2016
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“For example, the SASP produced by preneoplastic hepatocytes recruits immature myeloid cells that inhibit NK cells, therefore contributing to HCC progression (Eggert et al. 2016).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Eggert et al. 2016
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“p16 INK4a , p21 and a variety of SASP factors were detected in patient- derived non- malignant tissue surrounding the tumour boundaries of hepatocellular carcinoma lesions 90 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [90]
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“Via secretion of CCL2, hepatocytes with Nras G12V - induced senescence attracted a subset of CCR2 + myeloid cells that engaged cytotoxic NK cells, eventually blocking tumour immune surveillance 90 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [90]
In the citing paper
“in later stages the tumor cells block the maturation of the accumulated iMC which eventually promote the growth of established hepatocellular carcinoma by inhibiting NK cell functions (Eggert et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Eggert et al., 2016
In the citing paper
“in the initial stages, SASP mediated recruitment of immature myeloid cells (iMC) which when differentiated into macrophages clear the pre-malignant senescence cells to prevent cancer initiation.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Eggert et al., 2016
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“peritumoral tissue senescence has been associated with poor survival in patients with hepatocellular carcinoma [362].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [362]
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“There is convergent evidence that this occurs via the recruitment of myeloid-derived suppressor cells (MDSCs) chemoattracted by factors (e.g., IL-6, IL-8, and CCL2) secreted by senescent cells in murine models of HCC, 193 prostate, 194 and skin cancers.195”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [193]
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Metadata
- Authors
- Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., Heikenwalder, M., Wang, X. W., Zender, L., & Greten, T. F.
- Affiliations
- National Institutes of Health (US)
- University of Tübingen (DE)
- Universitätsklinikum Aachen (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Zender, Lars
- Greten, Tim F.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 30
- Issue
- 4
- Pages
- 533-547
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC7789819
- OpenAlex
- W2530995434
- Semantic Scholar
- 45e8e4d91cc1db28efeb781d9d19abda9935ae32
- Cited by
- 609
- References
- 40
- Citations by year
- 2026: 50 · 2025: 68 · 2024: 86 · 2023: 71 · 2022: 76 · 2021: 75 · 2020: 66 · 2019: 41 · 2018: 44 · 2017: 31 · 2016: 1
- FWCI
- 23.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- DFG (FOR2314, SFB685)
- Gottfried Wilhelm Leibniz Program
- European Research Council
- German Ministry for Education and Research
- German Universities Excellence Initiative
- German Center for Translational Cancer Research
- German-Israeli Cooperation in Cancer Research
- Stiftung Experimentelle Biomedizin
- Pre-clinical Comprehensive Center
- Helmholtz foundation
- NIH
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- oncogene-induced senescence, hepatocellular carcinoma, CCR2, myeloid cell recruitment, chemokines, NK cell inhibition, tumor progression, tumor initiation
- MeSH terms
- Animals, Female, Carcinoma, Hepatocellular, Humans, Immunologic Surveillance, Liver Neoplasms, Mice, Inbred BALB C, Mice, Inbred C57BL, Cellular Senescence, Mice, Knockout, Disease Progression, Mice
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