Involvement of alpha 1-2-fucosyltransferase I (FUT1) and surface-expressed Lewis(y) (CD174) in first endothelial cell-cell contacts during angiogenesis.
During the initiation of tumor associated angiogenesis endothelial cells migrate, adhere to extracellular matrix and form cell-cell contacts. Humoral factors of malignant cells conduct this process. We investigated whether cell surface expression of the carbohydrate blood group determinant Lewis(y) (CD174) and its precursor structure H2 (CD173) on endothelial cells is influenced by soluble factors of tumor cells. Using a bone marrow derived endothelial cell line we observed an enhanced expression of CD173/CD174 and transcription of FUT1, the key enzyme for their synthesis, after treatment with tumor necrosis factor-alpha (TNF-alpha) or conditioned supernatants of the leukemia cell line KG1a. CD173/CD174 are concentrated on pseudopodial extensions responsible for initial contacts between endothelial cells. Endothelial migration induced by TNF-alpha could be diminished by antibodies to CD174 as well as by siRNA induced downmodulation of FUT1 transcription. Endothelial FUT1-siRNA-transfectants displayed impaired in vitro angiogenesis when cultivated on extracellular matrix and in spheroid assays. In vivo upregulation of CD174 expression was observed immunocytologically in capillaries of tumor-infiltrated tissue. Together, our observations point to a tumor induced transcription of endothelial FUT1 and consequently an enhanced expression of CD174 which is involved in migration and early cell-cell contacts during tumor associated angiogenesis.
Moehler
Thomas M
TM
Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
Sauer
Sandra
S
Witzel
Maximilian
M
Andrulis
Mindaugas
M
Garcia-Vallejo
Juan J
JJ
Grobholz
Rainer
R
Willhauck-Fleckenstein
Martina
M
Greiner
Axel
A
Goldschmidt
Hartmut
H
Schwartz-Albiez
Reinhard
R
D000906:Antibodies / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002238:Carbohydrate Epimerases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism; D007983:Lewis Blood Group Antigens / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011498:Protein Precursors / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018874:Spheroids, Cellular; D013347:Subcellular Fractions / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D000906:Antibodies; D002238:Carbohydrate Epimerases; D003094:Collagen; D004338:Drug Combinations; D005647:Fucosyltransferases; D007797:Laminin; D007983:Lewis Blood Group Antigens; D011498:Protein Precursors; D011509:Proteoglycans; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C094162:Lewis Y antigen; C059485:matrigel