Abstract
BackgroundLung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood.Methodology/Principal FindingsHere, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype.Conclusions/SignificanceThese experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.
Highlights
The World Health Organization reports that approximately 1.25 billion people smoke cigarettes on a daily basis [1] and that smoking will cause roughly 10 million deaths per annum by the year 2030 [2]
We first mimicked the effects of chronic cigarette smoke exposure by repeatedly treating non-cancerous human bronchial epithelial BEAS-2B cells [10] with cigarette smoke extract (CSE) in culture
In this study we have shown that chronic exposure to cigarette smoke extract readily can damage lung epithelial cells, inducing hyperplasic growth, malignant cell transformation and carcinogenesis
Summary
The World Health Organization reports that approximately 1.25 billion people smoke cigarettes on a daily basis [1] and that smoking will cause roughly 10 million deaths per annum by the year 2030 [2]. We show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies
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