title: Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
abstract: Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: bid2004@med.cornell.edu.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Peipei
authors.initials: P
authors.lastname: Guo
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Sharrell B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Butler
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Casey
authors.affiliation: Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.affiliation: Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: srafii@med.cornell.edu.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism*; D016259:Genes, myc; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D034741:RNA, Small Interfering; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D051519:Fibroblast Growth Factor 4; C120420:Hey1 protein, mouse; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1; D016186:Receptor, Macrophage Colony-Stimulating Factor