title: Microenvironmental interactions between endothelial and lymphoma cells: a role for the canonical WNT pathway in Hodgkin lymphoma.
abstract: The interaction between vascular endothelial cells (ECs) and cancer cells is of vital importance to understand tumor dissemination. A paradigmatic cancer to study cell-cell interactions is classical Hodgkin Lymphoma (cHL) owing to its complex microenvironment. The role of the interplay between cHL and ECs remains poorly understood. Here we identify canonical WNT pathway activity as important for the mutual interactions between cHL cells and ECs. We demonstrate that local canonical WNT signaling activates cHL cell chemotaxis toward ECs, adhesion to EC layers and cell invasion using not only the Wnt-inhibitor Dickkopf, tankyrases and casein kinase 1 inhibitors but also knockdown of the lymphocyte enhancer binding-factor 1 (LEF-1) and β-catenin in cHL cells. Furthermore, LEF-1- and β-catenin-regulated cHL secretome promoted EC migration, sprouting and vascular tube formation involving vascular endothelial growth factor A (VEGF-A). Importantly, high VEGFA expression is associated with a worse overall survival of cHL patients. These findings strongly support the concept that WNTs might function as a regulator of lymphoma dissemination by affecting cHL cell chemotaxis and promoting EC behavior and thus angiogenesis through paracrine interactions.
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Linke
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Harenberg
authors.affiliation: Department of Medical Statistics, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nietert
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zaunig
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: von Bonin
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Arlt
authors.affiliation: Section Hematopathology, UKSH Campus Kiel, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Szczepanowski
authors.affiliation: Department of Chemical Biology, Helmholtz-Centre for Infection Research HZI, Braunschweig, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Weich
authors.affiliation: Institute of Pharmacology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lutz
authors.affiliation: Institute of Diagnostic and Interventional Radiology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: C
authors.identifier: 0000-0003-4297-8077
authors.initials: C
authors.lastname: Dullin
authors.affiliation: Faculty of Science, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Janovská
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Krafčíková
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Trantírek
authors.affiliation: Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Ovesná
authors.affiliation: Section Hematopathology, UKSH Campus Kiel, Kiel, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Department of Medical Statistics, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Beissbarth
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.|Institute of Diagnostic and Interventional Radiology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.|Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Alves
authors.affiliation: Faculty of Science, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic.|Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of Czech Republic, Brno, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Bryja
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Department of Anatomy and Cell Biology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wilting
authors.affiliation: Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kube
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D054415:Chemokine CCL19 / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism*; D006689:Hodgkin Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D054415:Chemokine CCL19; D051821:Lymphoid Enhancer-Binding Factor 1; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin