Original Article

Leukemia (2017) 31, 361–372; doi:10.1038/leu.2016.232; published online 4 October 2016

Lymphoma

Microenvironmental interactions between endothelial and lymphoma cells: a role for the canonical WNT pathway in Hodgkin lymphoma

F Linke1, M Harenberg1, M M Nietert2, S Zaunig1, F von Bonin1, A Arlt1, M Szczepanowski3, H A Weich4, S Lutz5, C Dullin6, P Janovská7, M Krafčíková8, L Trantírek8, P Ovesná9, W Klapper3, T Beissbarth2, F Alves1,6,10, V Bryja7,11, L Trümper1, J Wilting12 and D Kube1

  1. 1Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany
  2. 2Department of Medical Statistics, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany
  3. 3Section Hematopathology, UKSH Campus Kiel, Kiel, Germany
  4. 4Department of Chemical Biology, Helmholtz-Centre for Infection Research HZI, Braunschweig, Germany
  5. 5Institute of Pharmacology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany
  6. 6Institute of Diagnostic and Interventional Radiology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany
  7. 7Faculty of Science, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic
  8. 8Central European Institute of Technology, Masaryk University, Brno, Czech Republic
  9. 9Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic
  10. 10Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany
  11. 11Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of Czech Republic, Brno, Czech Republic
  12. 12Department of Anatomy and Cell Biology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany

Correspondence: Professor D Kube, Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Robert-Koch-Str. 40, Göttingen 37075, Germany. E-mail: dieter.kube@med.uni-goettingen.de

Received 25 May 2016; Revised 7 July 2016; Accepted 3 August 2016
Accepted article preview online 18 August 2016; Advance online publication 4 October 2016

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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.