Authors: Vivian Y. Shin¹; William K.K. Wu¹; Yi-Ni Ye¹; Wallace H.L. So¹; Marcel W.L. Koo¹; Edgar S.L. Liu¹; Jiing-Chyuan Luo²; Chi-Hin Cho¹

Source: Carcinogenesis, Volume 25, Number 12, December 2004 , pp. 2487-2495(9)

Publisher: Oxford University Press

Abstract:

Early studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 µg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50–200 µg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E<inf>2</inf> (PGE<inf>2</inf>) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE<inf>2</inf> release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/carcin/bgh266

Affiliations: 1: Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China and 2: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan

Publication date: 2004-12-01

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• Carcinogenesis is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal will publish papers that warrant prompt publication in the areas of Cancer Biology, Molecular Epidemiology and Cancer Prevention, and Carcinogenesis.

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