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

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 IκBα phosphorylation, IL-6 and TGFβ 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.

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

“…We previously showed that TLR2/MyD88 signaling in tumor cells promotes gastric tumorigenesis in gp130 F/F mice (19,28). Consistent with these findings, it has been shown that TLR2 signaling in cancer cells plays a tumor-promoting role through the enhancement of stemness (23,24). Moreover, the epithelial cell-specific deletion of Myd88 was observed to suppress intestinal tumorigenesis in Apc Min mice (16).…”

“…13,42). It has been reported that TLR2/4 recognize high-mobility group box 1 and extracellular matrix proteoglycan versican that are produced by cancer cells (24,43,44). Accordingly, cancer cell-derived ligands as well as infectious agents may We also showed that inflammatory responses induced the expression of TLR2 and CD14 in tumor epithelial cells (Fig.…”

“…Importantly, we show that MyD88 signaling in BMDCs is required for the generation of the inflammatory microenvironment in tumors even though the COX-2/PGE 2 pathway is activated. Moreover, inflammatory responses induce the expression of TLR2 and CD14 in tumor epithelial cells, which have been shown to play tumor-promoting roles through enhancement of stem cell properties (16,23,24). These results indicate that both the MyD88 signaling and the COX-2/PGE 2 pathway are required for generation of the inflammatory microenvironment, which may promote tumorigenesis through the induction of TLR2/ CD14 signaling in tumor cells.…”

NK cells control breast cancer and related cancer stem cell hematological spread

“…1A and B, respectively), as has already been observed in previous reports. 22,24 Moreover, tumorspheres showed increased in vitro self-renewal, with respect to TUBO cells in our own experiments. This is demonstrated by the higher number of cell clones generated by tumorspheres in a limiting dilution assay (Fig.…”

“…21 Previous data have shown that NK cells selectively kill CSCs derived from human colon carcinoma, 15 melanoma 16 and glioblastoma, 17 in mainly in vitro experiments. We herein describe in vitro and in vivo experiments which validate the NK cell targeting of breast tumor-derived CSCs using CSC-enriched tumorspheres 22 derived from an ErbB-2 C murine breast cancer tumor cell line (TUBO), 23 and murine and human triple negative breast cancer (TNBC) cell lines.…”