Pro-angiogenic Signaling by the Endothelial Presence of CEACAM1

Abstract

Here, we demonstrate the expression of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) in angiogenic sprouts but not in large mother blood vessels within tumor tissue. Correspondingly, only human microvascular endothelial cells involved in in vitro tube formation exhibit CEACAM1. CEACAM1-overexpressing versus CEACAM1-silenced human microvascular endothelial cells were used in migration and tube formation assays. CEACAM1-overexpressing microvascular endothelial cells showed prolonged survival and increased tube formation when they were stimulated with vascular endothelial growth factor (VEGF), whereas CEACAM1 silencing via small interfering RNA blocks these effects. Gene array and LightCycler analyses show an up-regulation of angiogenic factors such as VEGF, VEGF receptor 2, angiopoietin-1, angiopoietin-2, tie-2, angiogenin, and interleukin-8 but a down-regulation of collagen XVIII/endostatin and Tie-1 in CEACAM1-overexpressing microvascular endothelial cells. Western blot analyses confirm these results for VEGF and endostatin at the protein level. These results suggest that constitutive expression of CEACAM1 in microvascular endothelial cells switches them to an angiogenic phenotype, whereas CEACAM1 silencing apparently abrogates the VEGF-induced morphogenetic effects during capillary formation. Thus, strategies targeting the endothelial up-regulation of CEACAM1 might be promising for antiangiogenic tumor therapy.Angiogenesis is defined as sprouting of new blood vessels from preexisting blood vessels and is a prerequisite for tumor growth and metastasis. It is regulated by angiogenic activators and inhibitors (1, 2). The structural formation and maturation of blood vessels during vasculogenesis and angiogenesis is a very complex process that runs in successive steps including proliferation and tube formation of endothelial cells, construction of the basement membrane, integration of peri-endothelial cells into the vascular wall, and embedding of blood vessels into the peri-vascular tissue (3-6). Numerous angiogenic factors including vascular endothelial growth factor (VEGF), 1 fibroblast growth factor-2, angiopoietin (Ang)-1, Ang2 (3, 7-9), and their receptors, which belong to the receptor tyrosine kinase family, are involved in several steps of this process (8). Several other factors such as angiogenin (12) and interleukin-8 (13-16) promote angiogenesis.Also, cell adhesion molecules such as integrins (17-19), VEcadherin (20, 21), I-CAM (22-24), and V-CAM (25, 26) play a crucial role for capillary morphogenesis and functional modulation of blood vessels, such as the regulation of vascular permeability (27). The human carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), formerly known as biliary glycoprotein or CD66a in humans and C-CAM in rats, is a member of the carcinoembryonic antigen family, belongs to the immunoglobulin superfamily (28), and is a major carrier of SiLe X residues (29). It mediates cell adhesion via homophilic as well as heterophilic binding to other member...

CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer

“…Additionally, it was shown that CEACAM1 was enriched in tumor endothelial cells compared with whole lung tumor tissue using a subtracting proteomic mapping technique (Oh et al, 2004). Interestingly, our recent data demonstrate that CEACAM1 overexpression in human micro vascular endothelial cells leads to a significant upregulation of VEGF expression among other pro-angiogenic factors such as Ang1, Ang2, angiogenin and IL-8 (Kilic et al, 2005). This signalling switches endothelial cells to an angiogenic phenotype and demonstrates an inverse action of endothelial CEACAM1 in comparison to epithelial CEACAM1 signalling as demonstrated here by the overexpression of CEACAM1 in the prostate cancer cell line DU-145.…”

CEACAM1: a key regulator of vascular permeability

“…Because CEACAM1 plays a major role in angiogenesis and vascular integrity (Ergun et al, 2000;Kilic et al, 2005;Muller et al, 2005;Horst et al, 2006;Tilki et al, 2006;Kilic et al, 2007;Horst et al, 2009), we questioned whether the vascular permeability pathway and, more specifically, the eNOS/Akt pathway was dysregulated by CEACAM1. We measured NO release from COS-7 cells co-transfected with CEACAM1-L or CEACAM1-S, eNOS and VEGFR2.…”

“…Moreover, Muller and co-workers established that transmembrane CEACAM1-L expressed on endothelial cells was implicated in angiogenic activation by affecting cytoskeletal architecture and integrin-mediated signaling (Muller et al, 2005). Accordingly, CEACAM1 is expressed in newly formed vessels during physiological angiogenesis such as in wound healing and endometrial proliferation, as well as in immature new blood vessels of different tumors (Ergun et al, 2000;Kilic et al, 2005). Downregulation of epithelial CEACAM1-L in prostate intraepithelial neoplasia (PIN) was accompanied by its upregulation in adjacent vasculature, which correlated with vascular destabilization and increased vascularization of prostate tumors (Tilki et al, 2006).…”

CEACAM1 : modulateur central du métabolisme, de la progression tumorale,de l’angiogenèse et de l’immunité

“…CEACAM1 semble donc jouer un rôle primordial dans l'intégrité vasculaire et la formation de réseaux capillaires in vivo, particulièrement en situation de néovascularisation [21]. La surexpression de CEACAM1 à la surface de cellules endothéliales induit fortement l'expression de facteurs pro-angiogéniques tels que le VEGF, l'angiopoiétine-1 et -2, l'interleukine-8 (IL-8) ; et, à l'inverse, inhibe la production de facteurs anti-angiogéniques comme le collagène XVIII et l'endostatine [22]. Par ailleurs, CEACAM1 régule l'adhésion des cellules endothéliales sur la matrice extracellulaire via l'activation des protéines de la famille Rho et la voie de signalisation des intégrines [23].…”