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) due 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 EC.We demonstrate that local canonical WNT signaling activates cHL cell chemotaxis towards ECs, adhesion to EC layers and cell invasion using the Wnt-inhibitor Dickkopf, tankyrases and casein kinase inhibitors but also knock-down 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 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 regulator of lymphoma dissemination by affecting cHL cell chemotaxis and promoting endothelial cell behavior and thus angiogenesis through paracrine interactions.

No abstract