Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature.
Nucleolin is specifically transported to the surface of proliferating endothelial cells in vitro and in vivo. In contrast to its well defined functions in the nucleus and cytoplasm, the function of cell surface nucleolin is poorly defined. We have previously identified the nucleolin-binding antibody NCL3 that specifically binds to cell surface nucleolin on angiogenic blood vessels in vivo and is internalized into the cell. Here, we show that NCL3 inhibits endothelial tube formation in vitro as well as angiogenesis in the matrigel plaque assay and subcutaneous tumor models in vivo. Intriguingly, the specific targeting of proliferating endothelial cells by NCL3 in subcutaneous tumor models leads to the normalization of the tumor vasculature and as a result to an increase in tumor oxygenation. Treatment of endothelial cells with anti-nucleolin antibody NCL3 leads to a decrease of mRNA levels of the anti-apoptotic molecule Bcl-2 and as a consequence induces endothelial cell apoptosis as evidenced by PARP cleavage. These data reveal a novel mode of action for anti-angiogenic therapy and identify cell surface nucleolin as a novel target for combinatorial chemotherapy.
Fogal
Valentina
V
Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sugahara
Kazuki N
KN
Ruoslahti
Erkki
E
Christian
Sven
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D000097796:Nucleolin
D000906:Antibodies; D010100:Oxygen; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin