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ECigIntel - More study needed on complex nicotine-cancer links

Laypeople reading a new opinion paper in the journal Nature Reviews Cancer may be alarmed at its comment that there is “emerging evidence of direct contributions of nicotine to cancer onset and growth”.

“The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells,” says the paper.

Its author, Sergei Grando, a professor in the departments of dermatology and biological chemistry at the University of California at Irvine, says the paper “Connections of nicotine to cancer” is “most definitely the most complete review yet of nicotine and cancer”.

And Grando makes it clear that there are reasons to be concerned about the safety of nicotine not only in tobacco products, but also in e-cigs, where it is heated along with often undocumented ingredients.

But it is important to note that although nicotine can contribute to cancer, on its own the current evidence does not support a direct, carcinogenic link in “normal use”. While nicotine can play a role in the formation and development of tumours, such as by interfering with the body’s method of killing cancer cells, and promoting the growth of blood supplies to tumours, at low doses it is not likely to be of concern, although certain people may be more at risk than others.

Grando confirms this, noting that nicotine alone is “not very significant, unless used in high doses”. Critics of laboratory studies rightly point out that high doses of many substances could cause cancer, and that controls using other substances are not often used in experiments.

However, in Grando’s paper he says the cancer-inducing potential of nicotine with “long-term systematic administration” has not been evaluated, while he notes a study conducted by himself and colleagues where mice were injected with nicotine over two years with doses equivalent to Swedish snus users.

Nearly 80% of these mice did develop certain tumours, some of which could be attributable to nicotine, although again there are critics who argue that clinical studies on humans would be far more meaningful.

Guilty pleasure

Grando reviews in detail the evidence that nicotine does not just affect the neural “pleasure centres” of the brain but also “hits and potentially damages multiple non-neuronal targets”. One of the key mechanisms is the activation by nicotine of the nicotinic acetylcholine receptors. Acetylcholine is a “ubiquitous” chemical active in “numerous biological processes”; Grando explains how it doesn’t just exist in neural systems, and how nicotine binds with higher affinity than acetylcholine to these receptors (which are named nicotinic because of this affinity, although the body’s natural activating chemical is acetylcholine). Crucially, the receptors are also found on many non-neuronal cell types.

Nicotine may also directly permeate and affect cells, something which may be happening in the mouse study, but its “targets” here are not known, unlike the carcinogenic mechanisms of tobacco nitrosamines, which can cause certain mutations. Instead, much of Grando’s paper looks at the complex signalling mechanisms of the receptors, as this is where nicotine plays an obvious role and where there is a large volume of published research.

Mixed signals

This is where things get very complicated – the science of how the nicotinic receptors operate in both normal and cancer cells shows that there is much still to be studied on signalling pathways, gene expression and interaction with growth factors and hormones, among other issues.

Grando cites recent work by Bavarva and colleagues on altered expression of genes, many linked to cancer, after normal breast cells were subjected to nicotine, along with many other studies, on topics such as which signalling events are triggered by the receptor channels, and how nicotine is known to accelerate wound healing. Such effects could be undesirable in growth of tumours.

Another important discussion concerns genetic variations in the receptors, such that certain people have an increased risk of developing lung cancer, although again recent work has shown that some receptor subtypes may function as tumour suppressors. Grando says that about 20% of people worldwide have such genetic variation, and his paper notes a crucial fact that the aberrant receptors can predispose people to lung cancer regardless of whether they smoke tobacco.

Other areas of research include building on existing knowledge that nicotine can increase the survival of cancer cells, and their proliferation and spread; while there is “overwhelming evidence” that nicotine can play a part in tumour-supporting structures, such as the blood supply. There is also evidence that nicotine may add to resistance to chemotherapy and radiotherapy used to treat cancers.

Grando told ECigIntellgence that he feels the most important research directions now are:

  • Evaluation of the incidence of various types of cancer, not just lung cancer, and secondary tumours (relapses) in the users of nicotine products.
  • Elucidation of the dose- and time-dependent changes in the transcriptome, proteome and metabolome of the tobacco-related cancer-susceptible cell and tissue types.
  • Identification of the links between mutations of nicotinic receptors and various types of tobacco-related cancers.
  • Mitochondrial mechanisms of nicotine protection from chemo- and radiotherapies.

What This Means: The picture that emerges from this comprehensive review is that of many and often surprising effects of nicotine on the body, some of them beneficial (the medicinal uses of nicotine are also summarised in the paper).

Regarding links with cancer, current evidence suggests that high doses may be harmful over time, although how much, for how long and by what route (e.g. oral vs skin) are unknown factors. And those who are susceptible genetically to cancer may be more at risk, as nicotine could give a “second” hit to mutated receptors. Those undergoing cancer treatments may also be more at risk from nicotine-containing products.

The term “opinion” is rather misleading, as this is a highly complex scientific review paper full of descriptions of receptors, signalling pathways, gene expression and more; the 192 references are testimony to its thoroughness.

– Marc Beishon ECigIntelligence health correspondent

Photo: R. Reeves