期刊
CANCER CELL
卷 17, 期 3, 页码 262-272出版社
CELL PRESS
DOI: 10.1016/j.ccr.2009.12.043
关键词
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资金
- Boehringer Ingelheim Foundation
- European Union
- Deutsche Forschungsgemeinschaft [KFO105, TRR54]
- Deutsche Krebshilfe
Activated RAS/BRAF oncogenes induce cellular senescence as a tumor-suppressive barrier in early cancer development, at least in part, via an oncogene-evoked DNA damage response (DDR). In contrast, Myc activation-although producing a DDR as well-is known to primarily elicit an apoptotic countermeasure. Using the E mu-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor beta (TGF-beta) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-beta action, like genetic inactivation of the senescence-related histone methyltransferase Suv39h1, significantly accelerates Myc-driven tumor development via cancellation of cellular senescence. These findings, recapitulated in human aggressive B cell lymphomas, demonstrate that tumor-prompted stroma-derived signals may limit tumorigenesis by feedback senescence induction.
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