title: Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth.
abstract: Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ₃ as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Susan Q
authors.initials: SQ
authors.lastname: Ke
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: William
authors.initials: W
authors.lastname: Flavahan
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Paul
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Departments of Neurological Surgery &Pathology, University Hospitals, Case Medical Center &Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002630:Chemotactic Factors / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D005909:Glioblastoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008163:Luminescent Measurements; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D015815:Cell Adhesion Molecules; D002630:Chemotactic Factors; D039302:Integrin alphaVbeta3; C512835:POSTN protein, human; D034741:RNA, Small Interfering