Abstract
Abstract
While cellular senescence has long been recognized as an irreversible form of growth arrest, evidence in the literature has suggested that subpopulations of senescent tumor cells may retain proliferative capacity. To directly address this question, H460 non-small cell lung cancer cells induced into senescence by exposure to etoposide, and enriched based on β-galactosidase staining and size, were shown to recover reproductive capacity, which was accompanied by resolution of the DNA-damage-response (downregulation of p53 and p21Waf1/Cip1 induction), attenuation of the senescence-associated secretory phenotype (SASP) as well as downregulation of miRNA34 expression and an increase in c-myc. The senescence-enriched lung cancer cells were also capable of tumor growth upon transplantation into immunodeficient mice. Re-emergence from etoposide-induced senescence was also observed using HCT116 colon cancer cells, as evidenced by concomitant downregulation of a senescence-associated reporter (BTG1-RFP). Collectively, these findings indicate that therapy-induced senescence (TIS) may ultimately be a transient process in that at least a subpopulation of tumor cells can resume proliferation. We propose that some forms of tumor dormancy that lead to disease recurrence may reflect cells that enter into and ultimately escape from senescence.
Citation Format: Tareq Saleh, Moureq R. Alotaibi, Sarah L. Kyte, Emmanuel K. Cudjoe, Ajinkya Kawale, Jingwen Xu, Zeinab Elsayed, Joseph W. Landry, Scott C. Henderson, Vasily Yakovlev, Lynne W. Elmore, David A. Gewirtz. Therapy-induced senescence is reversible in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 459.