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. Sharpless & 2 others Hyman Muss, Judith Campisi

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages165-176
Number of pages12
JournalCancer Discovery
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2017

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Cell Aging
Recurrence
Drug Therapy
Neoplasms
Inflammation
Heart Neoplasms
Cell- and Tissue-Based Therapy
Pharmaceutical Preparations
Transgenic Mice
Fatigue
Bone Marrow
Cell Proliferation
T-Lymphocytes
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Oncology

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Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., ... Campisi, J. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discovery, 7(2), 165-176. DOI: 10.1158/2159-8290.CD-16-0241

Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. / Demaria, Marco; O’Leary, Monique N.; Chang, Jianhui; Shao, Lijian; Liu, Su; Alimirah, Fatouma; Koenig, Kristin; Le, Catherine; Mitin, Natalia; Deal, Allison M.; Alston, Shani; Academia, Emmeline C.; Kilmarx, Sumner; Valdovinos, Alexis; Wang, Boshi; De Bruin, Alain; Kennedy, Brian K.; Melov, Simon; Zhou, Daohong; Sharpless, Norman E.; Muss, Hyman; Campisi, Judith.

In: Cancer Discovery, Vol. 7, No. 2, 01.02.2017, p. 165-176.

Research output: Contribution to journalArticle

Demaria, M, O’Leary, MN, Chang, J, Shao, L, Liu, S, Alimirah, F, Koenig, K, Le, C, Mitin, N, Deal, AM, Alston, S, Academia, EC, Kilmarx, S, Valdovinos, A, Wang, B, De Bruin, A, Kennedy, BK, Melov, S, Zhou, D, Sharpless, NE, Muss, H & Campisi, J 2017, 'Cellular senescence promotes adverse effects of chemotherapy and cancer relapse' Cancer Discovery, vol 7, no. 2, pp. 165-176. DOI: 10.1158/2159-8290.CD-16-0241
Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discovery. 2017 Feb 1;7(2):165-176. Available from, DOI: 10.1158/2159-8290.CD-16-0241
Demaria, Marco ; O’Leary, Monique N. ; Chang, Jianhui ; Shao, Lijian ; Liu, Su ; Alimirah, Fatouma ; Koenig, Kristin ; Le, Catherine ; Mitin, Natalia ; Deal, Allison M. ; Alston, Shani ; Academia, Emmeline C. ; Kilmarx, Sumner ; Valdovinos, Alexis ; Wang, Boshi ; De Bruin, Alain ; Kennedy, Brian K. ; Melov, Simon ; Zhou, Daohong ; Sharpless, Norman E. ; Muss, Hyman ; Campisi, Judith. / Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. In: Cancer Discovery. 2017 ; Vol. 7, No. 2. pp. 165-176
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