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Leukemia. 2017 Feb;31(2):361-372. doi: 10.1038/leu.2016.232. Epub 2016 Aug 18.

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

Author information

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

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.

PMID:
27535218
DOI:
10.1038/leu.2016.232
[Indexed for MEDLINE]

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