Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis.
To examine the role of endothelial heparan sulfate during angiogenesis, we generated mice bearing an endothelial-targeted deletion in the biosynthetic enzyme N-acetylglucosamine N-deacetylase/N-sulfotransferase 1 (Ndst1). Physiological angiogenesis during cutaneous wound repair was unaffected, as was growth and reproductive capacity of the mice. In contrast, pathological angiogenesis in experimental tumors was altered, resulting in smaller tumors and reduced microvascular density and branching. To simulate the angiogenic environment of the tumor, endothelial cells were isolated and propagated in vitro with proangiogenic growth factors. Binding of FGF-2 and VEGF(164) to cells and to purified heparan sulfate was dramatically reduced. Mutant endothelial cells also exhibited altered sprouting responses to FGF-2 and VEGF(164), reduced Erk phosphorylation, and an increase in apoptosis in branching assays. Corresponding changes in growth factor binding to tumor endothelium and apoptosis were also observed in vivo. These findings demonstrate a cell-autonomous effect of heparan sulfate on endothelial cell growth in the context of tumor angiogenesis.
Fuster
Mark M
MM
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Wang
Lianchun
L
Castagnola
Janice
J
Sikora
Lyudmila
L
Reddi
Krisanavane
K
Lee
Phillip H A
PH
Radek
Katherine A
KA
Schuksz
Manuela
M
Bishop
Joseph R
JR
Gallo
Richard L
RL
Sriramarao
P
P
Esko
Jeffrey D
JD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D015238:Sulfotransferases / Q000172:deficiency / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D009363:Neoplasm Proteins; D015238:Sulfotransferases; D042461:Vascular Endothelial Growth Factor A; C021350:heparitin sulfotransferase