In recent years a growing demand for simple and robust SNP genotyping platforms has arisen from the widespread use of SNPs in industrial and public research. The resulting knowledge about genotype/phenotype correlations is of special interest for the identification of potential new drug targets and in the field of pharmacogenomics. However, full exploitation of the available genomic information requires vast numbers of SNP analyses, as large cohorts of patients have to be screened for a large number of markers. Only very few of the current SNP genotyping techniques can cope with the resulting demands concerning sample throughput, automation, accuracy and cost-effectiveness. MALDI-TOF mass spectrometry has the potential to develop into a 'Gold Standard' for high-throughput SNP genotyping - if it has not already done so. This review will focus on the latest developments of this technology.
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...
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.
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