Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer

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...

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Bibliographic Details
Published in:Molecular cancer research 2005-11, Vol.3 (11), p.607-615
Main Authors: Shin, Vivian Y, Wu, William K K, Chu, Kent-Man, Wong, Helen P S, Lam, Emily K Y, Tai, Emily K K, Koo, Marcel W L, Cho, Chi-Hin
Format: Article
Language:English
Subjects:
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Animals
Cell Division - drug effects
Cell Line, Tumor
Cell Movement - drug effects
Collagen
Cyclooxygenase 2 - metabolism
Cyclooxygenase-2
Drug Combinations
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Gastrointestinal cancers: stomach
Humans
Laminin
Matrix metalloproteinase
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Mice
Mice, Nude
Neoplasm Invasiveness - pathology
Neoplasm Transplantation
Neovascularization, Pathologic - metabolism
Neovascularization, Pathologic - pathology
Nicotine
Nicotine - pharmacology
Nicotinic Agonists - pharmacology
Proteoglycans
Receptors, Cell Surface - metabolism
Receptors, Urokinase Plasminogen Activator
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Surgical Sponges
Umbilical Veins - cytology
Urokinase-Type Plasminogen Activator - metabolism
Vascular endothelial growth factor receptor
Vascular Endothelial Growth Factor Receptor-2 - metabolism
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Summary: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 μg/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 ∼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.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.MCR-05-0106