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

DNA damage-mediated induction of a chemoresistant niche.

Author information

  • 1The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, 02139, USA.

Abstract

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.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID:
21029859
[PubMed - indexed for MEDLINE]
PMCID:
PMC2972353
Free PMC Article

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