title: Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway.
abstract: 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.
authors.affiliation: Department of Immunology, Nankai University, Tianjin, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Debbie
authors.initials: D
authors.lastname: Liao
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Dorothy
authors.initials: D
authors.lastname: Markowitz
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000950:Antigens, Ly; D018398:Homeodomain Proteins; D007093:Imidazoles; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011799:Quinazolines; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; C527783:Sox2 protein, mouse; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C101044:RTKI cpd; D009828:Oleanolic Acid; C541485:EGFR protein, mouse; D066246:ErbB Receptors