Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence

Cancer Cell. 2010 Mar 16;17(3):262-72. doi: 10.1016/j.ccr.2009.12.043.


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 Emu-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cellular Senescence / physiology*
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Macrophage Activation
  • Macrophages / metabolism
  • Methyltransferases / metabolism*
  • Methyltransferases / physiology
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Proto-Oncogene Proteins c-myc / physiology
  • Repressor Proteins / metabolism*
  • Repressor Proteins / physiology
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Protein p53 / physiology


  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Suv39h1 protein, mouse
  • Methyltransferases