Lymphatic reprogramming of microvascular endothelial cells by CEA-related cell adhesion molecule-1 via interaction with VEGFR-3 and Prox1.
Here, we demonstrate that carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is expressed and co-localized with podoplanin in lymphatic endothelial cells (LECs) of tumor but not of normal tissue. CEACAM1 overexpression in human dermal microvascular endothelial cells (HDMECs) results in a significant increase of podoplanin-positive cells in fluorescence-activated cell sorting analyses, while such effects are not observed in CEACAM1 overexpressing human umbilical vein endothelial cell (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 vascular endothelial growth factor C, -D (VEGF-C, -D) and their receptor vascular endothelial growth factor receptor 3 (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 small interfering RNA 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.
Kilic
Nerbil
N
Internal Medicine, Department of Hematology/Oncology/Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Oliveira-Ferrer
Leticia
L
Neshat-Vahid
Samira
S
Irmak
Ster
S
Obst-Pernberg
Kirstin
K
Wurmbach
Jan-Henner
JH
Loges
Sonja
S
Kilic
Ergin
E
Weil
Joachim
J
Lauke
Heidrun
H
Tilki
Derya
D
Singer
Bernhard B
BB
Ergün
Süleyman
S
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D004729:Endothelium, Lymphatic / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008833:Microcirculation; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000098:blood supply; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein; D000098853:Podoplanin
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors; D000098551:Prospero-Related Homeobox 1 Protein; C069847:CD66 antigens; C117468:PDPN protein, human; D000098853:Podoplanin