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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Cell Communication*
  • Cell Line
  • Cell Movement / genetics
  • Chemokine CCL19 / metabolism
  • Chemotaxis / genetics
  • Chemotaxis / immunology
  • Endothelial Cells / metabolism*
  • Hodgkin Disease / genetics
  • Hodgkin Disease / immunology
  • Hodgkin Disease / metabolism*
  • Hodgkin Disease / pathology*
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Neovascularization, Pathologic
  • Tumor Microenvironment* / genetics
  • Tumor Microenvironment* / immunology
  • Vascular Endothelial Growth Factor A / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Chemokine CCL19
  • Lymphoid Enhancer-Binding Factor 1
  • Vascular Endothelial Growth Factor A
  • beta Catenin