title: Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells.
abstract: Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and aggresiveness of tumor stem-like cells (TSCs) expressing IGF1 receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R+TSCs to express FGF4, inducing a feedforward FGFR1-ETS2 angiocrine cascade that obviates TEC IGFBP7. Thus, loss of IGFBP7 and upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and converts naive tumor cells to chemoresistant TSCs, thereby facilitating their invasiveness and progression.
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Birth Defects and Related Diseases of Women and Children, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: zhc2007@med.cornell.edu.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Inghirami
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Birth Defects and Related Diseases of Women and Children, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: bid2004@med.cornell.edu.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: srafii@med.cornell.edu.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000502:physiology; D051519:Fibroblast Growth Factor 4 / Q000502:physiology; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D050787:Proto-Oncogene Protein c-ets-2 / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology
chemical_list: C494069:ETS2 protein, human; C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D018969:Insulin-Like Growth Factor Binding Proteins; D050787:Proto-Oncogene Protein c-ets-2; C102529:insulin-like growth factor binding protein-related protein 1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: ETS2; IGFBP7/angiomodullin; angiocrine factors; cancer stem cells; chemoresistance; insulin growth factor-1; tumor aggressiveness; tumor endothelial cell; tumor microenvironment; vascular niche