The High mobility group box 1/Toll-like Receptor 2 axis plays a non-inflammatory role in the self-renewal of mammary cancer stem cells

Abstract

The lack of effective treatment in several metastatic cancers raises the question of whether current therapies target the right cells. These treatments may be missing cancer stem cells (CSC), a sub-population of stem cell-like cells that are able to play a critical role in cancer progression. A profound understanding of the mechanisms that regulate CSC selfrenewal is therefore essential for the identification of new CSC antigens that may turn out to be the ideal target for more effective anticancer strategies. In the light of these considerations, we have performed the transcription profiling of the murine ErbB2+ breast tumor cell line TUBO versus its derived CSC-enriched mammospheres. Of the all antigens that have been identified, we have focused our attention on toll-like receptor (TLR)2 which has been identified as being overexpressed in CSC. Moreover, TLR2 plays a central role in CSC biology; it is a key molecule for CSC selfrenewal as its signaling inhibition impairs in vitro mammosphere generation and blocks tumorigenesis and lung metastases development in vivo. Our in-depth analysis of the downstream signal driven by TLR2 has demonstrated that it is activated by endogenous high mobility-group box (HMGB)1 with an autocrine loop, which induces IkB? phosphorylation, IL-6 and TGF? secretion and consequently STAT3 and Smad3 activation.