Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

M. Demaria, M. N. O'Leary, J. Chang, L. Shao, S. Liu, F. Alimirah, K. Koenig, C. Le, N. Mitin, A. M. Deal, S. Alston, E. C. Academia, S. Kilmarx, A. Valdovinos, B. Wang, A. de Bruin, B. K. Kennedy, S. Melov, D. Zhou, N. E. SharplessH. Muss, J. Campisi

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phe- notype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, 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 infl ammation. 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 fi ndings in mice, the risk of chemotherapy-induced fatigue was signifi cantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These fi ndings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.
Original languageEnglish
Pages (from-to)165-176
Number of pages12
JournalCancer Discovery
Volume7
Issue number2
DOIs
Publication statusPublished - 2016

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

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Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., ... Campisi, J. (2016). Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discovery, 7(2), 165-176. https://doi.org/10.1158/2159-8290.CD-16-0241
Demaria, M. ; O'Leary, M. N. ; Chang, J. ; Shao, L. ; Liu, S. ; Alimirah, F. ; Koenig, K. ; Le, C. ; Mitin, N. ; Deal, A. M. ; Alston, S. ; Academia, E. C. ; Kilmarx, S. ; Valdovinos, A. ; Wang, B. ; de Bruin, A. ; Kennedy, B. K. ; Melov, S. ; Zhou, D. ; Sharpless, N. E. ; Muss, H. ; Campisi, J. / Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. In: Cancer Discovery. 2016 ; Vol. 7, No. 2. pp. 165-176.
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abstract = "Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phe- notype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, 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 infl ammation. 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 fi ndings in mice, the risk of chemotherapy-induced fatigue was signifi cantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These fi ndings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.",
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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 2016, 'Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse', Cancer Discovery, vol. 7, no. 2, pp. 165-176. https://doi.org/10.1158/2159-8290.CD-16-0241

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. / Demaria, M.; O'Leary, M. N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A. M.; Alston, S.; Academia, E. C.; Kilmarx, S.; Valdovinos, A.; Wang, B.; de Bruin, A.; Kennedy, B. K.; Melov, S.; Zhou, D.; Sharpless, N. E.; Muss, H.; Campisi, J.

In: Cancer Discovery, Vol. 7, No. 2, 2016, p. 165-176.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

AU - Demaria, M.

AU - O'Leary, M. N.

AU - Chang, J.

AU - Shao, L.

AU - Liu, S.

AU - Alimirah, F.

AU - Koenig, K.

AU - Le, C.

AU - Mitin, N.

AU - Deal, A. M.

AU - Alston, S.

AU - Academia, E. C.

AU - Kilmarx, S.

AU - Valdovinos, A.

AU - Wang, B.

AU - de Bruin, A.

AU - Kennedy, B. K.

AU - Melov, S.

AU - Zhou, D.

AU - Sharpless, N. E.

AU - Muss, H.

AU - Campisi, J.

PY - 2016

Y1 - 2016

N2 - Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phe- notype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, 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 infl ammation. 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 fi ndings in mice, the risk of chemotherapy-induced fatigue was signifi cantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These fi ndings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.

AB - Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phe- notype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, 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 infl ammation. 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 fi ndings in mice, the risk of chemotherapy-induced fatigue was signifi cantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These fi ndings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.

U2 - 10.1158/2159-8290.CD-16-0241

DO - 10.1158/2159-8290.CD-16-0241

M3 - Article

C2 - 27979832

VL - 7

SP - 165

EP - 176

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 2

ER -