Submitted June 25, 2007
Accepted August 24, 2007
Lymphatic reprogramming of micro vascular endothelial cells by CEA-related Cell Adhesion Molecule-1 via interaction with VEGFR-3 and Prox1
Nerbil Kilic, Leticia Oliveira-Ferrer, Samira Neshat-Vahid, Ster Irmak, Kirstin Obst-Pernberg, Jan-Henner Wurmbach, Sonja Loges, Ergin Kilic, Joachim Weil, Heidrun Lauke, Derya Tilki, Bernhard B Singer, and Suleyman Ergun*
Internal Medicine, Department of Hematology/Oncology/Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Institute of Anatomy I, University Hospital Essen, Essen, Germany
Institute of Anatomy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Department of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Department of Cardiology, University Hospital Lubeck, Lubeck, Germany
Department of Urology, University Hospital Grosshadern, Munich, Germany
* Corresponding author; email: sueleyman.erguen{at}uk-essen.de.
Here, we demonstrate that CEACAM1 is expressed and co-localized with podoplanin in lymphatic endothelial cells (LECs) of tumor but not of normal tissue. CEACAM1 overexpression in HDMECs results in a significant increase of podoplanin positive cells in FACS analyses while such effects are not observed in CEACAM1 overexpressing HUVECs. This effect of CEACAM1 is ceased when HDMECs are transfected with CEACAM1/y-- missing the tyrosine residues in its cytoplasmic domain. CEACAM1 overexpression in HDMECs leads to an up-regulation of VEGF-C, -D and their receptor VEGFR-3 at mRNA and protein levels. HDMECs transfected with CEACAM1 but not those with CEACAM1/y-- show enhanced expression of the lymphatic markers Prox1, Podoplanin and LYVE-1. Furthermore, Prox1 silencing in HDMECs via siRNA blocks the CEACAM1-induced increase of VEGFR-3 expression. Number and network of endothelial tubes induced by VEGF-C and -D are enhanced in CEACAM1-overexpressing HDMECs. Moreover, VEGF-A treatment of CEACAM1-silenced HDMECs restores their survival but not that with VEGF-C- and VEGF-D. These data imply that the interaction of CEACAM1 with Prox1 and VEGFR-3 plays a crucial role in tumor lymphangiogenesis and reprogramming of vascular endothelial cells to LECs. CEACAM1-induced signaling effects appear to be dependent on the presence of tyrosine residues in the CEACAM1 cytoplasmic domain.
