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 language | English |
|---|---|
| Pages (from-to) | 4731-4744 |
| Number of pages | 14 |
| Journal | FASEB Journal |
| Volume | 27 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2013 |
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Keywords
- BOXA
- Breast carcinoma
- Endogenous TLR2 ligands
- MyD88
- NFB
- Transcriptome
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology
Cite this
The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells. / Conti, Laura; Lanzardo, Stefania; Arigoni, Maddalena; Antonazzo, Roberta; Radaelli, Enrico; Cantarella, Daniela; Calogero, Raffaele A.; Cavallo, Federica.
In: FASEB Journal, Vol. 27, No. 12, 12.2013, p. 4731-4744.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells
AU - Conti, Laura
AU - Lanzardo, Stefania
AU - Arigoni, Maddalena
AU - Antonazzo, Roberta
AU - Radaelli, Enrico
AU - Cantarella, Daniela
AU - Calogero, Raffaele A.
AU - Cavallo, Federica
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - BOXA
KW - Breast carcinoma
KW - Endogenous TLR2 ligands
KW - MyD88
KW - NFB
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=84890540571&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890540571&partnerID=8YFLogxK
U2 - 10.1096/fj.13-230201
DO - 10.1096/fj.13-230201
M3 - Article
C2 - 23970797
AN - SCOPUS:84890540571
VL - 27
SP - 4731
EP - 4744
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 12
ER -