Cellular senescence promotes adverse effects of chemotherapy and cancer relapse

Marco Demaria, Monique N. O’Leary, Jianhui Chang, Lijian Shao, Su Liu, Fatouma Alimirah, Kristin Koenig, Catherine Le, Natalia Mitin, Allison M. Deal, Shani Alston, Emmeline C. Academia, Sumner Kilmarx, Alexis Valdovinos, Boshi Wang, Alain De Bruin, Brian K. Kennedy, Simon Melov, Daohong Zhou, Norman E. SharplessHyman Muss, Judith Campisi

Research output: Contribution to journalArticlepeer-review

837 Scopus citations

Abstract

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short-and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. SIGNIFICANCE: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy.

Original languageEnglish (US)
Pages (from-to)165-176
Number of pages12
JournalCancer Discovery
Volume7
Issue number2
DOIs
StatePublished - Feb 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Cellular senescence promotes adverse effects of chemotherapy and cancer relapse'. Together they form a unique fingerprint.

Cite this