A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal.
Cell Rep
; 25(13): 3706-3720.e8, 2018 12 26.
Article
em En
| MEDLINE
| ID: mdl-30590043
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
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Inibidores da Angiogênese
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Proteoma
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Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article