Tumor cell senescence response produces aggressive variants

Tumors often respond favorably to initial chemotherapy but eventually relapse with drug resistance and increased metastatic potential. Cellular senescence is a major therapeutic outcome of cancer chemotherapy, which leads to tumor stasis or regression through immune clearance of senescent cells. However, senescent tumor cells have been shown to resume proliferation at low frequency. We found that subjecting arrested senescent tumor cells to cytotoxic treatments stimulates the clonogenic proliferation of remaining survivors. The senescence revertants showed a reduced rate of proliferation but increased migration and invasion potential in vitro, and increased tumorigenic potential in vivo. Gene expression profiling showed that the senescence revertants are distinct from both parental and senescent cells. A subset of senescence-activated genes remains active in the revertants. These genes are implicated in regulating cell motility, invasion, and metastasis, which may collectively contribute to the aggressiveness of the revertants. The findings suggest that although therapy-induced senescence has short-term benefits, the response also causes reprogramming of gene expression and activates invasion-related genes that accelerate tumor progression.