DNA damage-mediated induction of a chemoresistant niche

Cell. 2010 Oct 29;143(3):355-66. doi: 10.1016/j.cell.2010.09.043.


While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Burkitt Lymphoma / drug therapy*
  • Burkitt Lymphoma / metabolism
  • Burkitt Lymphoma / pathology*
  • Cell Culture Techniques
  • Cell Survival
  • Cellular Senescence
  • Culture Media, Conditioned
  • Cytokines / analysis
  • Cytokines / metabolism
  • DNA Damage*
  • Doxorubicin / therapeutic use
  • Drug Resistance, Neoplasm*
  • Endothelial Cells / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Janus Kinase 2 / metabolism
  • Liver Neoplasms / pathology
  • Mice
  • Neoplasm, Residual / metabolism
  • Neoplasm, Residual / pathology
  • Paracrine Communication*
  • Thymus Gland / chemistry
  • Thymus Gland / cytology
  • Thymus Gland / metabolism*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • p38 Mitogen-Activated Protein Kinases


  • Culture Media, Conditioned
  • Cytokines
  • Interleukin-6
  • Tissue Inhibitor of Metalloproteinase-1
  • Doxorubicin
  • Janus Kinase 2
  • p38 Mitogen-Activated Protein Kinases