Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

Abstract

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells non-specifically, 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 anti-cancer treatments.