DNA Damage-Mediated Induction of a Chemoresistant Niche

Abstract

Summary 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.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

“…27 There is some evidence that antibody-dependent cellular cytotoxicity mediated by activation of natural-killer cells contributes to the clinical response to rituximab. 28 Investigators have postulated that intensive chemotherapy could compromise the effi cacy of rituximab by impairing immune cellular mechanisms.…”

Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

“…Both treatments damage DNA, which can generate a secretory phenotype in untransformed cells in the tumor microenvironment [12]. It was recently shown that the secretory phenotype of untransformed cells after DNA damaging chemotherapy could create a chemo-resistant niche for the remaining tumor cells [13]. Specifically, Timp-1, and, highly relevant to the secretory phenotype of senescent cells that we will describe further, IL-6, were acutely secreted by thymic endothelial cells in response to DNA damage.…”

Distinctive properties of metastasis-initiating cells

“…Besides these MIC-intrinsic properties, tumor-associated stroma has also been found to severely increase resistance to traditional cancer therapies (Gilbert and Hemann 2010;Sun et al 2012). In metastasis, primary tumor-associated endothelial cells produce TNFα to increase CXCL1/2 in cancer cells.…”