Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo.
Senescence is a distinct cellular response induced by DNA-damaging agents and other sublethal stressors and may provide novel benefits in cancer therapy. However, in an ageing model, senescent fibroblasts were found to stimulate the proliferation of cocultured cells. To address whether senescence induction in cancer cells using chemotherapy induces similar effects, we used GFP-labelled prostate cancer cell lines and monitored their proliferation in the presence of proliferating or doxorubicin-induced senescent cancer cells in vitro and in vivo. Here, we show that the presence of senescent cancer cells increased the proliferation of cocultured cells in vitro through paracrine signalling factors, but this proliferative effect was significantly less than that seen with senescent fibroblasts. In vivo, senescent cancer cells failed to increase the establishment, growth or proliferation of LNCaP and DU145 xenografts in nude mice. Senescent cells persisted as long as 5 weeks in tumours. Our results demonstrate that although drug-induced senescent cancer cells stimulate the proliferation of bystander cells in vitro, this does not significantly alter the growth of tumours in vivo. Coupled with clinical observations, these data suggest that the proliferative bystander effects of senescent cancer cells are negligible and support the further development of senescence induction as therapy.
Ewald
Ja
J
Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
Desotelle
Ja
J
Almassi
N
N
Jarrard
Df
D
D000818:Animals; D024201:Bystander Effect; D049109:Cell Proliferation; D016922:Cellular Senescence; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D004317:Doxorubicin