A chemotherapy-associated senescence bystander effect in breast cancer cells

Abstract

A bystander effect typically refers to the death, altered growth or damage of cells that have not directly received chemotherapy or irradiation. Cancer cells derived from solid tumors readily undergo senescence in response to chemotherapeutic agents, prompting us to test for the existence of a senescence bystander effect. MCF-7 breast cancer cells were acutely exposed to Adriamycin to trigger senescence. Naïve MCF-7 cells, when cultured in conditioned media from senescent breast cancer cells, growth arrested despite mitogenic stimulation and exhibited SA-β-galactosidase activity, an enlarged cell size and stable upregulation of p21 WAF1 protein, collectively indicating a senescent state. In contrast, HCT-116 colon cancer cells, which also undergo p53-mediated senescence in response to acute AdR, did not undergo growth inhibition or senescence when cultured with conditioned media from senescent HCT-116 cells. Reciprocal experiments indicated that naïve HCT-116 cells, like MCF-7 cells, are susceptible to the growth inhibitory effects of a breast cancer-derived mediator, which is independent of residual drug in conditioned media. Our study reveals a novel action of Adriamycin, which may contribute to its potent anti-breast cancer activity and lead to the discovery of additional therapeutic targets for the exploitation of a senescence bystander effect.

Plasminogen activator inhibitor 1 - insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence

“…As reported previously (9), conditioned medium from doxorubicintreated, senescent MCF-7 breast cancer cells inhibited the proliferation of naive MCF-7 cells (Fig. 1A) and induced senescence phenotype in these cells (Fig.…”

“…Senescent cancer cells are characterized by proliferation arrest, flat and enlarged morphology, and SA β-gal activity, which is similar to the senescence phenotype of primary cells. A previous report demonstrated that naive MCF-7 breast cancer cells undergo senescence upon exposure to conditioned medium from senescent MCF-7 cells induced to senesce by treatment with doxorubicin, a widely used chemotherapeutic drug for breast cancer (9). This observation suggested the presence of secreted mediator(s) of senescence in the conditioned medium of senescent MCF-7 cells, which may contribute to the potent anticancer activity of doxorubicin.…”

HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

“…We propose that early breast hyperplasia engages microenvironmental responses from infiltrating immune cells, or other stromal components that lead to persistent JAK/STAT3-signaling and a tumor suppressive arrest (Figure 3). The senescent cells, themselves, may then secrete additional cytokines that lead to a wide-spread senescence through a bystander effect [76,77,78,79]. The prototype molecule for OIS studies is mutant RAS.…”

IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘Bystander senescence’

“…Given that senescent cells produce these cytokine species frequently in a simultaneous fashion, it is not unexpected that such DNA damage-promoting cytokine environment can induce senescent cells in their neighborhood by paracrine effects (‘bystander senescence’; [47]) as has been documented in several experimental settings [48, 49]. However, the mechanisms underlying bystander senescence are currently unclear.…”