Tumor‐Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox‐2 Signaling Pathway

The cancer stem cell (CSC) hypothesis has gained significant recognition as a descriptor of tumorigenesis. Additionally, tumor‐associated macrophages (TAMs) are known to promote growth and metastasis of breast cancer. However, it is not known whether TAMs mediate tumorigenesis through regulation of...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2013-02, Vol.31 (2), p.248-258
Main Authors: Yang, Jian, Liao, Debbie, Chen, Cong, Liu, Yan, Chuang, Tsung‐Hsien, Xiang, Rong, Markowitz, Dorothy, Reisfeld, Ralph A., Luo, Yunping
Format: Article
Language:English
Subjects:
Animals
Antigens, Ly - genetics
Antigens, Ly - metabolism
Apoptosis - drug effects
ATP Binding Cassette Transporter, Sub-Family G, Member 2
ATP-Binding Cassette Transporters - genetics
ATP-Binding Cassette Transporters - metabolism
Breast cancer
Cancer stem cells
Cell Communication - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Transformation, Neoplastic - drug effects
Female
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Imidazoles - pharmacology
Macrophages - drug effects
Macrophages - metabolism
Macrophages - pathology
Mammary Neoplasms, Animal - genetics
Mammary Neoplasms, Animal - metabolism
Mammary Neoplasms, Animal - pathology
Medical research
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Nanog Homeobox Protein
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Octamer Transcription Factor-3 - genetics
Octamer Transcription Factor-3 - metabolism
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - pharmacology
Proteins
Quinazolines - pharmacology
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
RNA, Small Interfering - genetics
Side population cells
Signal Transduction - drug effects
SOXB1 Transcription Factors - antagonists & inhibitors
SOXB1 Transcription Factors - genetics
SOXB1 Transcription Factors - metabolism
STAT
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Stem cell‐microenvironment interactions
Transcription factors
Tyrphostins - pharmacology
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Summary:The cancer stem cell (CSC) hypothesis has gained significant recognition as a descriptor of tumorigenesis. Additionally, tumor‐associated macrophages (TAMs) are known to promote growth and metastasis of breast cancer. However, it is not known whether TAMs mediate tumorigenesis through regulation of breast CSCs. Here, we report that TAMs promote CSC‐like phenotypes in murine breast cancer cells by upregulating their expression of Sox‐2. These CSC‐like phenotypes were characterized by increased Sox‐2, Oct‐4, Nanog, AbcG2, and Sca‐1 gene expression, in addition to increased drug‐efflux capacity, resistance to chemotherapy, and increased tumorigenicity in vivo. Downregulation of Sox‐2 in tumor cells by siRNA blocked the ability of TAMs to induce these CSC‐like phenotypes and inhibited tumor growth in vivo. Furthermore, we identified a novel epidermal growth factor receptor (EGFR)/signal transducers and activators of transcription 3 (Stat3)/Sox‐2 paracrine signaling pathway between macrophages and mouse breast cancer cells that is required for macrophage‐induced upregulation of Sox‐2 and CSC phenotypes in tumor cells. We showed that this crosstalk was effectively blocked by the small molecule inhibitors AG1478 or CDDO‐Im against EGFR and Stat3, respectively. Therefore, our report identifies a novel role for TAMs in breast CSC regulation and establishes a rationale for targeting the EGFR/Stat3/Sox‐2 signaling pathway for CSC therapy. STEM CELLS2013;31:248–258
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1281