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Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
- Source :
-
Cancer discovery [Cancer Discov] 2017 Feb; Vol. 7 (2), pp. 165-176. Date of Electronic Publication: 2016 Dec 15. - Publication Year :
- 2017
-
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.<br />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. Cancer Discov; 7(2); 165-76. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.<br />Competing Interests: All other authors declare no financial interests.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Breast Neoplasms genetics
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cell Proliferation drug effects
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Female
Humans
Mice
Mice, Transgenic
Neoplasm Recurrence, Local
Antineoplastic Agents adverse effects
Breast Neoplasms drug therapy
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p16 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 7
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 27979832
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-16-0241