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Mechanisms of Disease: signal transduction in lung carcinogenesis—a comparison of smokers and never-smokers

Nature Clinical Practice Oncology volume 5, pages 610–618 (2008)Cite this article

Abstract

Although smoking has been established as the most important cause of lung cancer, approximately 10% of patients with this malignancy have no history of smoking. The pathogenesis of tobacco-related lung carcinogenesis is becoming well characterized, but the molecular mechanisms of neoplastic transformation in never-smokers have not yet been adequately elucidated. Nevertheless, numerous recent studies have revealed a distinct biological process of malignant transformation with unique epidemiological and clinicopathological characteristics in never-smokers. The molecular pathways involved in the differential pattern of lung oncogenesis according to smoking status, however, remain fairly obscure. Researchers have studied several molecular pathways implicated in lung carcinogenesis in smokers and never-smokers, examining these processes at the genomic, epigenetic and proteomic level. The differential protein expression according to smoking status in critical signal transduction pathways has attracted scientific interest because of the possibilities of therapeutic intervention. In this Review we describe the best-characterized signaling pathways implicated in the transduction of proliferative signals and discuss the activity of these pathways in smokers and never-smokers.

Key Points

  • Numerous recent studies have revealed a distinct biological process of malignant transformation with unique epidemiological and clinicopathological characteristics in never-smokers with lung cancer

  • Almost all cases of lung cancer in never-smokers are adenocarcinomas; these tumors tend to be diagnosed at more-advanced stages and are more likely to occur in women than in men compared with tumors in smokers

  • Never-smokers have a higher probability of EGFR mutations in exons 19 and 21 and are more likely to derive clinical benefit from therapy with tyrosine kinase inhibitors than are smokers

  • It is probable that the mitogenic effects of EGFR mutations in never-smokers are mediated via mitogen-activated protein kinase and, in particular, selective activation of p38; the Ras/Raf/mitogen-activated protein kinase pathway might constitute a critical mediator of extracellular signals or growth factors in never-smokers with lung cancer

  • In smokers, tobacco-induced KRAS mutations are responsible for the transduction of proliferative signals to the nucleus, possibly via an EGFR-independent pathway

  • A better comprehension of the distinct biological entities among patients with lung cancer might help identify potential new molecular targets for a more-selective therapeutic strategy

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Authors and Affiliations

  1. G Mountzios is a Medical Oncologist in the Department of Clinical Therapeutics at the University Hospital Alexandra, Athens, Greece,

    Giannis Mountzios

  2. P Fouret is Professor of Pathology and Head of the Laboratory of Translational Research and J-C Soria is Professor of Medicine and Medical Oncology in the Department of Medicine, both at Université Paris XI, Institut Gustave Roussy, Paris, France.,

    Pierre Fouret & Jean-Charles Soria

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  1. Giannis Mountzios
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Correspondence to Giannis Mountzios.

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Mountzios, G., Fouret, P. & Soria, JC. Mechanisms of Disease: signal transduction in lung carcinogenesis—a comparison of smokers and never-smokers. Nat Rev Clin Oncol 5, 610–618 (2008). https://doi.org/10.1038/ncponc1181

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