Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of
malignancies such as
colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible
cyclo-oxygenase (COX-2) in
tumor-associated angiogenesis and
tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics
tumor angiogenesis and is COX-2 and
vascular endothelial growth factor (
VEGF) dependent. In this model,
VEGF expression was down-regulated by selective COX-2 inhibition with
NS-398. To find out the involvement of COX-2/
VEGF pathway in
tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or
Lewis lung carcinoma cells. Daily
oral administration of
NS-398 or of
aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial
tumors with extensive angiogenesis markedly suppressed by
aspirin and
COX-2 inhibitors NS-398 and JTE522, but not by
mofezolac, an inhibitor of constitutive COX-1.
Tumor-associated angiogenesis was also significantly suppressed by a
neutralizing antibody against
VEGF. S-180
tumor growth in the subcutaneous tissues was also suppressed by
aspirin, COX-2 selective inhibitors, and the
VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/
VEGF-dependent pathway was effective in
tumor-associated angiogenesis,
tumor growth, and
tumor metastasis.