Journal
LEUKEMIA
Volume 31, Issue 2, Pages 361-372Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.232
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Funding
- Deutsche Forschungsgemeinschaft within the Forschergruppe [Ku 954/12-1, FOR942]
- CEITEC [LQ1601]
- Ministry of Education, Youths and Sports of the Czech Republic from the National Programme for Sustainability II funds
- BMBF e:Bio Project MetastaSys [0316173]
- BMBF e:Med Project MMML-Demonstrators [031A428B]
- German Research Foundation [SFB1002 TPC02]
- AZV CR, Ministry of Health, Czech Republic [NR 15-29793A]
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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 beta-catenin in cHL cells. Furthermore, LEF-1- and beta-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.
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