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.

Central European Institute of Technology Masaryk University Brno Czech Republic

Clinic of Hematology and Medical Oncology University Medical Centre of the Georg August University of Göttingen Göttingen Germany

Department of Anatomy and Cell Biology University Medical Centre of the Georg August University of Göttingen Göttingen Germany

Department of Chemical Biology Helmholtz Centre for Infection Research HZI Braunschweig Germany

Department of Cytokinetics Institute of Biophysics Academy of Sciences of Czech Republic Brno Czech Republic

Department of Medical Statistics University Medical Centre of the Georg August University of Göttingen Göttingen Germany

Department of Molecular Biology of Neuronal Signals Max Planck Institute for Experimental Medicine Göttingen Germany

Faculty of Science Institute of Experimental Biology Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic

Institute of Diagnostic and Interventional Radiology University Medical Centre of the Georg August University of Göttingen Göttingen Germany

Institute of Pharmacology University Medical Centre of the Georg August University of Göttingen Göttingen Germany

Section Hematopathology UKSH Campus Kiel Kiel Germany

Zobrazit více v PubMed

Leukemia. 2012 Oct;26(10):2269-76 PubMed

Blood. 2001 Aug 1;98(3):762-70 PubMed

Gut. 2016 Oct;65(10):1690-701 PubMed

Semin Cancer Biol. 2014 Feb;24:15-22 PubMed

Blood. 1993 Jul 1;82(1):262-7 PubMed

Mol Cancer Ther. 2014 Apr;13(4):833-41 PubMed

Genes Immun. 2001 Dec;2(8):433-41 PubMed

Blood. 2010 Oct 21;116(16):2975-83 PubMed

Leuk Lymphoma. 2015 May;56(5):1286-94 PubMed

Mol Carcinog. 2015 May;54(5):333-50 PubMed

Carcinogenesis. 2013 Mar;34(3):667-77 PubMed

Am J Pathol. 2013 Apr;182(4):1092-8 PubMed

Hematol Oncol. 2009 Mar;27(1):31-9 PubMed

Science. 2005 Jan 7;307(5706):58-62 PubMed

J Exp Med. 2008 Sep 29;205(10):2251-68 PubMed

Leuk Lymphoma. 2014 Mar;55(3):558-64 PubMed

Cell. 2009 Jul 10;138(1):51-62 PubMed

Front Physiol. 2014 Mar 05;5:75 PubMed

Cell Adh Migr. 2011 May-Jun;5(3):215-9 PubMed

Biochem Biophys Res Commun. 2001 Oct 19;288(1):8-15 PubMed

Blood. 2014 Nov 6;124(19):2973-82 PubMed

Hematol Rep. 2010 Jan 26;2(1):e3 PubMed

Cell. 2011 Mar 4;144(5):646-74 PubMed

Science. 1997 Mar 21;275(5307):1787-90 PubMed

J Pathol. 2010 Jul;221(3):248-63 PubMed

Nat Genet. 2005 Apr;37(4):382-90 PubMed

Oncogene. 2013 Apr 25;32(17):2230-8 PubMed

Cancer Res. 2001 Aug 15;61(16):6050-4 PubMed

Blood. 2002 Feb 15;99(4):1109-16 PubMed

Acta Biochim Biophys Sin (Shanghai). 2005 Mar;37(3):173-80 PubMed

J Pathol. 2002 Aug;197(5):677-83 PubMed

Cancer Metastasis Rev. 1993 Sep;12(3-4):303-24 PubMed

Br J Haematol. 2001 Sep;114(3):616-23 PubMed

Blood. 2008 Dec 15;112(13):5171-9 PubMed

Genesis. 2005 Aug;42(4):253-62 PubMed

Leuk Res. 2004 Jun;28(6):595-604 PubMed

Blood. 2013 Feb 28;121(9):1644-50 PubMed

Cell. 2004 Mar 19;116(6):883-95 PubMed

Nature. 2011 May 19;473(7347):298-307 PubMed

Blood. 2007 Nov 1;110(9):3102-11 PubMed

N Engl J Med. 2010 Mar 11;362(10):875-85 PubMed

Oncogene. 2017 Jan 5;36(1):13-23 PubMed

J Exp Med. 2001 May 7;193(9):1105-12 PubMed

Blood. 2002 Apr 15;99(8):2977-84 PubMed

Leuk Res. 2014 Aug;38(8):857-61 PubMed

Biol Reprod. 2005 Dec;73(6):1135-46 PubMed

Blood. 1996 Nov 1;88(9):3299-305 PubMed

J Clin Oncol. 2011 May 10;29(14):1812-26 PubMed

J Exp Med. 1987 Oct 1;166(4):1125-31 PubMed

Blood. 2013 Dec 19;122(26):4237-45 PubMed

Blood. 2015 Sep 10;126(11):1394-7 PubMed

Wnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomas