Blockade of angiogenesis is a promising strategy to suppress
tumor growth, invasion, and
metastasis.
Vascular endothelial growth factor (
VEGF), which binds to
tyrosine kinase receptors [
VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and
mitogen for endothelial cells.
Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of
nicotine on
gastric cancer growth. However, the action of
nicotine and the relationship between COX-2 and
VEGF/VEGFR system in
tumorigenesis remain undefined. In this study, the effects of
nicotine in
tumor angiogenesis, invasiveness, and
metastasis were studied with sponge implantation and
Matrigel membrane models.
Nicotine (200 microg/mL) stimulated
gastric cancer cell proliferation, which was blocked by
SC-236 (a highly selective
COX-2 inhibitor) and
CBO-P11 (a VEGFR inhibitor). This was associated with decreased
VEGF levels as well as
VEGFR-2 but not
VEGFR-1 expression. Topical injection of
nicotine enhanced
tumor-associated vascularization, with a concomitant increase in
VEGF levels in sponge implants. Again, application of
SC-236 (2 mg/kg) and
CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore,
nicotine enhanced
tumor cell invasion through the
Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with
gastric cancer cells. The activity of
matrix metalloproteinases 2 and 9 and
protein expressions of
plasminogen activators (
urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by
nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of
nicotine on angiogenesis,
tumor invasion, and
metastasis is COX-2/
VEGF/VEGFR dependent.