The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells

Laura Conti, Stefania Lanzardo, Maddalena Arigoni, Roberta Antonazzo, Enrico Radaelli, Daniela Cantarella, Raffaele A. Calogero, Federica Cavallo

Research output: Contribution to journalArticle

Abstract

Cancer stem cells (CSCs) are responsible for tumor progression, metastases, resistance to therapy, and tumor recurrence. Therefore, the identification of molecules involved in CSC self-renewal is a necessary step toward more effective therapies. To this aim, through the transcription profiling of the murine ErbB2 tumor cell line TUBO vs. derived CSC-enriched mammospheres, Toll-like receptor 2 (TLR2) was identified as 2-fold overexpressed in CSCs, as confirmed by qPCR and cytofluorimetric analysis. TLR2 signaling inhibition impaired in vitro mammosphere generation in murine TUBO (60%) and 4T1 (30%) and human MDA-MB-231 (50%), HCC1806 (60%), and MCF7 (50%) cells. In CSC, TLR2 was activated by endogenous high-mobility-group box 1 (HMGB1), inducing IB phosphorylation, IL-6 and TGF secretion, and, consequently, STAT3 and Smad3 activation. In vivo TLR2 inhibition blocked TUBO tumor takes in 9/14 mice and induced a 2-fold reduction in lung metastases development by decreasing cell proliferation and vascularization and increasing apoptosis. Collectively, these results demonstrate that murine and human mammary CSCs express TLR2 and its ligand HMGB1; this autocrine loop plays a pivotal role in CSC self-renewal, tumorigenesis, and metastatic ability. These findings, while providing evidence against the controversial use of TLR2 agonists in antitumor therapy, lay out new paths toward the design of anticancer treatments.-Conti, L., Lanzardo, S., Arigoni, M., Antonazzo, R., Radaelli, E., Cantarella, D., Calogero, R. A., Cavallo, F. The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells.

Original languageEnglish
Pages (from-to)4731-4744
Number of pages14
JournalFASEB Journal
Volume27
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • BOXA
  • Breast carcinoma
  • Endogenous TLR2 ligands
  • MyD88
  • NFB
  • Transcriptome

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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    Conti, L., Lanzardo, S., Arigoni, M., Antonazzo, R., Radaelli, E., Cantarella, D., Calogero, R. A., & Cavallo, F. (2013). The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells. FASEB Journal, 27(12), 4731-4744. https://doi.org/10.1096/fj.13-230201