期刊
MOLECULAR CANCER RESEARCH
卷 19, 期 4, 页码 651-666出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-1181
关键词
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资金
- NIH/NCI [F30 CA224979, T32 GM007250]
- US NIH [R01CA138421]
- American Cancer Society [RSG CCG-122517]
- Case Comprehensive Cancer Center [P30 CA43703]
The study demonstrates that inflammatory cytokines can induce cellular senescence and promote the formation of cancer stem cells. By combining CDK4/6 inhibition with senolytic therapy, cancer stem cells can be efficiently killed.
Although frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGFfi effector, SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSCs can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers.
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