Therapy-induced senescence in cancer

Abstract

Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.

Figure 1

Proliferating and drug-induced senescent PC3 prostate cancer cells. Senescent cancer cells exhibit the characteristic morphology and increased SA-β-gal activity seen in replicative senescent cells. PC3 cells were cultured in drug-free medium or in medium containing 250 nM quinone diaziquone for 3 days followed by 2 days in drug-free medium (13), fixing, and staining (12). Cells were visualized under ×200 magnification using phase contrast microscopy. Scale bar = 100 μm; SA-β-gal = senescence-associated β-galactosidase.