title: Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells.
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.
authors: Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. jinushi@igm.hokudai.ac.jp
authors: Masahisa
authors: M
authors: Jinushi
authors: Shigeki
authors: S
authors: Chiba
authors: Hironori
authors: H
authors: Yoshiyama
authors: Kenkichi
authors: K
authors: Masutomi
authors: Ichiro
authors: I
authors: Kinoshita
authors: Hirotoshi
authors: H
authors: Dosaka-Akita
authors: Hideo
authors: H
authors: Yagita
authors: Akinori
authors: A
authors: Takaoka
authors: Hideaki
authors: H
authors: Tahara
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008894:Milk Proteins / Q000235:genetics / Q000276:immunology; D018448:Models, Immunological; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D053823:Hedgehog Proteins; D015850:Interleukin-6; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse