title: Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
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.
  
  
  
  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. Cancer Discov; 7(2); 165-76. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
authors.affiliation: Buck Institute for Research on Aging, Novato, California. jcampisi@buckinstitute.org jcampisi@lbl.gov m.demaria@umcg.nl.|European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Monique N
authors.initials: MN
authors.lastname: O'Leary
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Fatouma
authors.initials: F
authors.lastname: Alimirah
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Kristin
authors.initials: K
authors.lastname: Koenig
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Le
authors.affiliation: HealthSpan Diagnostics, Research Triangle Park, North Carolina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mitin
authors.affiliation: The Lineberger Comprehensive Cancer Center and Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.affiliation: The Lineberger Comprehensive Cancer Center and Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Shani
authors.initials: S
authors.lastname: Alston
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Emmeline C
authors.initials: EC
authors.lastname: Academia
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Sumner
authors.initials: S
authors.lastname: Kilmarx
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Alexis
authors.initials: A
authors.lastname: Valdovinos
authors.affiliation: European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Boshi
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pathobiology, University of Utrecht, Utrecht, the Netherlands.|Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.affiliation: Buck Institute for Research on Aging, Novato, California.
authors.forename: Simon
authors.initials: S
authors.lastname: Melov
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: The Lineberger Comprehensive Cancer Center and Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: The Lineberger Comprehensive Cancer Center and Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Hyman
authors.initials: H
authors.lastname: Muss
authors.affiliation: Buck Institute for Research on Aging, Novato, California. jcampisi@buckinstitute.org jcampisi@lbl.gov m.demaria@umcg.nl.|Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16