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Cited by 28Angiogenesis and VEGF in CancerTelomeres, Telomerase, and SenescenceTGF-β signaling in diseases

A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

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Mastri, Michalis, Tracz, Amanda, Lee, Christina R., Dolan, Melissa, Attwood, Kristopher, Christensen, James G., Liu, Song, Ebos, John M.L.·2018·Cell Reports
DOI 10.1016/j.celrep.2018.12.017PMC PMC13277708
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Abstract

VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies ("senotherapeutics")-particularly those that block SASP regulation-may improve outcomes in patients after VEGFR TKI failure.

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  • Continuous transcriptional or functional changes in senescent cells, and the permanent need to actively maintain senescence-supporting transcription, puts the stability of cell cycle arrest at risk, occasionally leading to restoration of proliferative properties with a potentially detrimental effect on tumour suppression.

    “Continuous transcriptional or, more generally, functional changes in senescent cells, and the permanent need to actively maintain senescencesupporting transcription puts the stability of cell cycle arrest at risk, occasionally leading to the restoration of proliferative properties with a potentially detrimental effect on tumour suppression 5,79 .”

    From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [79]

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Authors
Mastri, M., Tracz, A., Lee, C. R., Dolan, M., Attwood, K., Christensen, J. G., Liu, S., & Ebos, J. M. L.
Affiliations
  • Roswell Park Comprehensive Cancer Center (US)
  • Sunnybrook Research Institute (CA)
  • Pfizer (United States) (US)
Corresponding author
Ebos, John M.L.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-12
Volume
25
Issue
13
Pages
3706-3720.e8
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2018.12.017
PMC
PMC13277708
OpenAlex
W2906196013
Cited by
28
References
15
Citations by year
2026: 1 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 2
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XWH-14-1-0210)
  • American Cancer Society (IRG-14-194-11SUB, RSG-18-064-01-TBG)
  • National Cancer Institute (P30CA016056)
  • Roswell Park Cancer Institute
  • Roswell Park Alliance Foundation, Roswell Park Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
senescence-associated secretory phenotype, VEGFR inhibitors, secretome, drug resistance, mTOR, interleukin-6, senotherapeutics, tumor progression
MeSH terms
Animals, Humans, Mice, Inbred BALB C, Neoplasm Metastasis, Neoplasms, Phenotype, Interleukin-6, Cellular Senescence, Drug Resistance, Neoplasm, Angiogenesis Inhibitors, Proteome, Receptors, Vascular Endothelial Growth Factor, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, TOR Serine-Threonine Kinases

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