Despite evidence that it is responsible for ∼3,000 deaths per year in the United States alone, there is still some debate about just how harmful passive smoking really is. This is due, in part, to a gap in our knowledge about the mechanisms by which the inhalation of environmental tobacco smoke (ETS) might cause cancer. A study by John Cooke and colleagues now indicates that ETS promotes tumour growth and angiogenesis, strengthening the link between passive smoking and cancer.

Cooke and co-workers exposed mice that had been injected with lung tumour cells to ETS and studied the effects of this on tumour growth and angiogenesis. They saw an increase in tumour growth in these mice that was five times greater than that in unexposed animals. The exposed mice also showed an increase in tumour blood-vessel density that was double that seen in control mice, indicating that components of ETS promote angiogenesis.

Nicotine is one of the main components of ETS and, although it is only a weak carcinogen, there is evidence that it can promote tumour development through indirect mechanisms. It has recently been shown that nicotine can induce angiogenesis by activating nicotinic acetylcholine receptors (nAchRs) on the surface of endothelial cells, which stimulates their proliferation and the subsequent formation of blood vessels. To test whether increases in tumour size and angiogenesis in mice exposed to ETS were due to the effects of nicotine, Cooke and colleagues tested whether this effect could be blocked by mecamylamine, an inhibitor of nAchRs. When exposed mice were treated with this drug, the formation of new blood vessels was almost completely abolished, indicating that nicotine has a key role in the induction of angiogenesis by ETS.

The authors also investigated the effect of ETS on the levels of two other angiogenesis promoters, monocyte chemoattractant protein 1 (MCP1) and vascular endothelial growth factor (VEGF). Increased levels of both of these proteins were found in serum from exposed mice. Mecamylamine blocked the increase in VEGF levels by approximately two-thirds, indicating that nicotine induces angiogenesis through VEGF signalling as well as by having a direct effect on endothelial cells. However, mecamylamine had little effect on MCP1 levels, indicating that other compounds that are present in ETS in addition to nicotine can stimulate angiogenesis.

Statins — which are best known for their use in treating high cholesterol levels — are potential angiogenesis inhibitors as they inhibit the secretion of MCP1 and interfere with signalling downstream of the VEGF receptor. Cooke and colleagues tested the effect of one of these molecules, cerivastatin, on tumour development in mice that were exposed to ETS. Cerivastatin substantially blocked the increases in both tumour size and angiogenesis in these mice, indicating a possible method of counteracting the harmful effects of inhaling this type of smoke.

Interestingly, the effects of ETS described here indicate a role for nicotine in promoting the growth of existing tumours rather than in initiating tumour formation. This indicates that it acts in concert with other more strongly carcinogenic ETS components to exert its harmful effects. The authors estimate that the levels of nicotine and other toxic chemicals that are present in the ETS used in these experiments were similar to those that are encountered by people in smoky environments such as bars and casinos. This study therefore provides compelling evidence that passive smoking can stimulate tumour growth and that it does indeed pose a serious threat to human health.