Abstract
Recent evidence has unveiled the critical role of tumor cells with stem cell activities in tumorigenicity and drug resistance, but how tumor microenvironments regulate cancer stem/initiating cells (CSCs) remains unknown. We clarified the role of tumor-associated macrophages (TAMs) and their downstream factor milk-fat globule-epidermal growth factor-VIII (MFG-E8) in the regulation of CSC activities. Bone marrow chimeric systems and adoptive cell transfers elucidated the importance of MFG-E8 from TAMs in conferring to CSCs with the ability to promote tumorigenicity and anticancer drug resistance. MFG-E8 mainly activates signal transducer and activator of transcription-3 (Stat3) and Sonic Hedgehog pathways in CSCs and further amplifies their anticancer drug resistance in cooperation with IL-6. Thus, the pharmacological targeting of key factors derived from tumor-associated inflammation provides a unique strategy to eradicate therapy-resistant tumors by manipulating CSC activities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antigens, Surface / genetics
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Antigens, Surface / immunology
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Hedgehog Proteins / immunology
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Humans
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Interleukin-6 / immunology
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Macrophages / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Milk Proteins / genetics
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Milk Proteins / immunology
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Models, Immunological
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / immunology*
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Neoplasms / pathology*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / immunology*
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Neoplastic Stem Cells / pathology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / genetics
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology
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Signal Transduction / immunology
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Tumor Microenvironment / immunology
Substances
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Antigens, Surface
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Hedgehog Proteins
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Interleukin-6
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Mfge8 protein, mouse
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Milk Proteins
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse