Abstract
A soluble form of the L1 cell adhesion molecule (sL1) is released from various tumor cells and can be found in serum and ascites fluid of uterine and ovarian carcinoma patients. sL1 is a ligand for several Arg-Gly-Asp (RGD)-binding integrins and can be deposited in the extracellular matrix. In this study we describe a novel function of this physiologically relevant form of L1 as a pro-angiogenic factor. We demonstrated that the anti-L1 monoclonal antibody (mAb) chCE7 binds near or to the sixth Ig-like domain of human L1 which contains a single RGD sequence. mAb chCE7 inhibited the RGD-dependent adhesion of ovarian carcinoma cells to sL1 and reversed the sL1-induced proliferation, matrigel invasion and tube formation of bovine aortic endothelial (BAE) cells. A combination of sL1 with vascular endothelial growth factor-A (VEGF-A(165)), which is an important angiogenic inducer in tumors, strongly potentiated VEGF receptor-2 tyrosine phosphorylation in BAE cells. Chick chorioallantoic membrane (CAM) assays revealed the pro-angiogenic potency of sL1 in vivo which could be abolished by chCE7. These results indicate an important role of released L1 in tumor angiogenesis and represent a novel function of antibody chCE7 in tumor therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenic Proteins / metabolism*
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Animals
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Antibodies, Monoclonal
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Cattle
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chickens
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Chorioallantoic Membrane / blood supply
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Chorioallantoic Membrane / drug effects
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Collagen / metabolism
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Drug Combinations
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Female
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Fibronectins / chemistry
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Humans
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Laminin / metabolism
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Neoplasms / blood supply
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Neoplasms / metabolism*
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Neovascularization, Pathologic / metabolism*
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Neural Cell Adhesion Molecule L1 / chemistry
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Neural Cell Adhesion Molecule L1 / immunology
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Neural Cell Adhesion Molecule L1 / metabolism*
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Oligopeptides / metabolism
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Protein Structure, Tertiary
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Proteoglycans / metabolism
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Repetitive Sequences, Amino Acid
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Solubility / drug effects
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Angiogenic Proteins
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Antibodies, Monoclonal
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Drug Combinations
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Fibronectins
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Laminin
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Neural Cell Adhesion Molecule L1
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Oligopeptides
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Proteoglycans
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Vascular Endothelial Growth Factor A
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matrigel
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arginyl-glycyl-aspartic acid
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Collagen
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Vascular Endothelial Growth Factor Receptor-2