Inhaled nicotine and lung cancer: Potential role of the nicotinic acetylcholine receptor

The article by Tang et al. (1) shows electronic-cigarette smoke (ECS) causes lung cancer and bladder hyperplasia in mice. Tang et al. (1) should be congratulated for their research contributing to this body of work, raising concerns about the effect of ECS on the lungs (1, 2). We outline below why we think nicotine may be directly carcinogenic when inhaled into the lungs and how this would explain why low levels of nitrosamines provide no comfort with regard to the safety of ECS (1).

Tang et al. (1) make important findings in this and earlier work (1, 2). First, lung cancer developed in the mice inhaling nicotine mixed with vehicle but not vehicle alone. Second, the mice that developed lung cancer were not more prone to developing bladder hyperplasia, suggesting a divergence in the effect of inhaled nicotine on the lungs and bladder. Third, inhaling nicotine resulted in a reduction in the DNA repair in the lung but not in the bladder. This suggests the effect of nicotine, from ECS, might be directly carcinogenic. We provide evidence that the nicotinic acetylcholine receptor (nAChR), consistently linked to lung cancer in large genetic studies, might mediate carcinogenesis through directly binding nicotine (and nitrosamines) in the airways epithelium (3–5).

Large epidemiological case–control studies published in 2008 showed that a genetic variant in the gene encoding a subunit of the nAChR receptor (CHRNA 3/5) was associated with lung cancer (3). This finding has been confirmed in a large prospective study (6). Also in 2008, we showed the same CHRNA variant (rs16969968) was associated with chronic obstructive pulmonary disease (COPD), another closely related complication of smoking involving inflammation-mediated remodeling of the respiratory epithelium (7). We have confirmed this dual association in a large prospective study of 10,000 high-risk smokers, showing this association between the nicotinic receptor (CHRNA) variant and lung cancer was independent of its association with COPD and cigarette exposure (8). This variant has been shown to have important effects on the receptor function, including mediating inflammatory effects initiated by cigarette smoke and linked to COPD (9, 10). It would be very interesting for Tang et al. (1) to examine the ECS relationship with lung cancer in mice exposed to nicotine-containing ECS where this gene has been altered. Nicotine and the nAChR are not implicated in recent cases of acute lung injury and deaths, following exposure to vitamin E acetate in illicit vape fluids.

The scientific implications derived from the observation that inhaled nicotine (or nitrosamines) may be directly carcinogenic and proinflammatory in the lungs are significant and challenge current views on the pathogenesis of lung cancer (7, 8) and COPD, respectively (9, 10). While the procarcinogenic effects of traditional cigarettes derived from the combustion of tobacco have been considered the primary drivers of lung cancer, nicotine itself must now be considered a direct carcinogen (7–10). The public health implications of this are even greater given the highly unregulated environment in which electronic cigarettes are currently being marketed around the world (1, 7). Further studies are urgently needed to clarify the potential harmful effects of inhaled nicotine in the development of lung cancer and COPD.