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Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphoma-genesis via Suv39h1-Dependent Senescence

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Jenuwein,  Thomas
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Reimann, M., Lee, S., Loddenkemper, C., Dörr, J. R., Tabor, V., Aichele, P., et al. (2010). Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphoma-genesis via Suv39h1-Dependent Senescence. Cancer Cell, 17, 262-272.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-8E99-2
Abstract
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 Eμ-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor β (TGF-β) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-β 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.