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-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.
Shin
Vivian Y
VY
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, Hong Kong.
Wu
William K K
WK
Chu
Kent-Man
KM
Wong
Helen P S
HP
Lam
Emily K Y
EK
Tai
Emily K K
EK
Koo
Marcel W L
MW
Cho
Chi-Hin
CH
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011509:Proteoglycans; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D015503:Surgical Sponges; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D004338:Drug Combinations; D007797:Laminin; D018722:Nicotinic Agonists; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C059485:matrigel; D009538:Nicotine; D003094:Collagen; D051546:Cyclooxygenase 2; D040301:Vascular Endothelial Growth Factor Receptor-2; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9