p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells.
The finding of frequent nitric oxide synthase expression in human cancers indicates that nitric oxide has a pathophysiological role in carcinogenesis. To determine the role of nitric oxide in tumor progression, we generated human carcinoma cell lines that produced nitric oxide constitutively. Cancer cells expressing inducible nitric oxide synthase that had wild-type p53 had reduced tumor growth in athymic nude mice, whereas those with mutated p53 had accelerated tumor growth associated with increased vascular endothelial growth factor expression and neovascularization. Our data indicate that tumor-associated nitric oxide production may promote cancer progression by providing a selective growth advantage to tumor cells with mutant p53, and that inhibitors of inducible nitric oxide synthase may have therapeutic activity in these tumors.
Ambs
S
S
Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Merriam
W G
WG
Ogunfusika
M O
MO
Bennett
W P
WP
Ishibe
N
N
Hussain
S P
SP
Tzeng
E E
EE
Geller
D A
DA
Billiar
T R
TR
Harris
C C
CC
D000818:Animals; D017209:Apoptosis; D016228:Endothelial Growth Factors / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse