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ToxSci Advance Access originally published online on March 16, 2007
Toxicological Sciences 2007 97(2):279-287; doi:10.1093/toxsci/kfm060
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nicotine Promotes Colon Tumor Growth and Angiogenesis through ß-Adrenergic Activation

Helen Pui Shan Wong*, Le Yu{dagger}, Emily Kai Yee Lam*, Emily Kin Ki Tai*, William Ka Kei Wu{dagger},{ddagger} and Chi-Hin Cho{dagger},1

* Department of Pharmacology, The University of Hong Kong, Hong Kong, China {dagger} Department of Pharmacology {ddagger} Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China

1 To whom correspondence should be addressed. Fax: +852-2603-5139; E-mail: chcho{at}cuhk.edu.hk.

Received December 28, 2006; accepted February 26, 2007


  Abstract

Cigarette smoking is a putative environmental risk factor for colon cancer. Nicotine, an active alkaloid in tobacco, has been implicated in carcinogenesis. In the present study, we demonstrated that oral nicotine administration (50 or 200 µg/ml) for 25 days stimulated growth of human colon cancer xenograft in nude mice. It also increased vascularization in the tumors and elevated cotinine and adrenaline plasma levels. ß-Adrenoceptors, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and vascular endothelial growth factor (VEGF) in tumor tissues were also increased by nicotine. I.p. injection of ß1-selective antagonist (atenolol, 5 or 10 mg/kg) or ß2-selective antagonist (ICI 118,551, 5, or 10 mg/kg) blocked the nicotine-stimulated tumor growth dose dependently, in which ß2-selective antagonist produced a more prominent effect. ß-Adrenoceptors blockade also abrogated the stimulatory action of nicotine on microvessel densities as well as cell expression of COX-2, PGE2, and VEGF, in which ß2-selective antagonist produced a significant effect. These findings provide a direct evidence that nicotine can enhance colon tumor growth mediated partly by stimulation of ß-adrenoceptors, preferentially the ß2-adrenoceptors. Activation of ß-adrenoceptors and the subsequent stimulation of COX-2, PGE2, and VEGF expression is perhaps an important mechanism in the tumorigenic action of nicotine on colon tumor growth. These data suggest that ß-adrenoceptors play a modulatory role in the development of colon cancer and partly elucidate the carcinogenic action of cigarette smoke.

Key Words: colon cancer; nicotine; ß-adrenoceptors; smoking.


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