Yang Leixiang, Fang Jia, Chen Jiandong
Molecular Oncology Department, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Tumor Biology Department, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA.
Cell Death Discov. 2017 Aug 21;3:17049. doi: 10.1038/cddiscovery.2017.49. eCollection 2017.
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 , and increased tumorigenic potential . 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.
肿瘤通常对初始化疗反应良好，但最终会因耐药性和转移潜能增加而复发。细胞衰老 是癌症化疗的主要治疗结果，它通过衰老细胞的免疫清除导致肿瘤停滞或消退。然而，已表明衰老肿瘤细胞会以低频率恢复增殖。我们发现，对停滞的衰老肿瘤细胞进行细胞毒性治疗会刺激剩余存活细胞的克隆增殖。衰老逆转细胞的增殖速率降低，但迁移和侵袭潜能增加，且致瘤潜能增加。基因表达谱分析表明，衰老逆转细胞与亲代细胞和衰老细胞均不同。一部分衰老激活基因在逆转细胞中仍保持活跃。这些基因与调节细胞运动、侵袭和转移有关，可能共同导致逆转细胞的侵袭性。这些发现表明，尽管治疗诱导的衰老有短期益处，但这种反应也会导致基因表达重编程并激活加速肿瘤进展的侵袭相关基因。
