3.3 Smoking and cancer

Two expert bodies, the International Agency for Research on Cancer (IARC) and the US Surgeon General’s office, periodically examine the evidence on smoking and cancer and issue comprehensive reports. Reports from both the IARC in 2004 and Surgeon General in 2014 stated that smoking causes cancers of the lung, upper aerodigestive tract (oral cavity, larynx, pharynx and oesophagus), pancreas, bladder, kidney, liver, cervix and stomach, and acute myeloid leukaemia.^{1, 2} The Surgeon General’s report also concluded that smoking causes colorectal cancer. In 2011 a Canadian expert panel concluded that smoking increases breast cancer risk but this conclusion was not shared by the IARC in its monograph from 2012.^{3, 4} The Surgeon General’s report also highlighted an association between smoking and breast cancer, but concluded that there is insufficient evidence to infer a causal relationship.² Details of the links between smoking and these cancers are discussed in Chapter 3, Section 3.4 (Lung cancer) and Section 3.5 (Other cancers).

In this section the mechanisms by which smoking causes cancer are summarised. Lung cancer is used as an example because it is one of the most thoroughly investigated cancers. Although more than 85% of lung cancers are attributable to smoking, not all smokers develop lung cancer and lung cancer does occur in non-smokers. In fact, lung cancer in non-smokers is believed to be a different disease from lung cancer in smokers.⁵ A compelling explanation of cancer causation needs to reflect these observations and the summary presented here also discusses the issue of individual susceptibility to cancer.

This section draws heavily on the US Surgeon General’s 2010 report How Tobacco Smoke Causes Disease: The Biology and Behavioural Basis for Smoking-Attributable Diseases.⁶ Unless otherwise referenced, the information herein has been sourced from this report.

3.3.1 Carcinogens in cigarette smoke

A carcinogen is any substance that contributes to the formation of cancer. Carcinogens include a wide variety of chemicals, naturally-occurring compounds and radioactive substances. They are not necessarily toxic in the short term; their damage after exposure may take years to become apparent.⁷ Carcinogens can be classified into two categories: genotoxic compounds that cause changes (mutations) in DNA sequences, and non-genotoxic carcinogens that act by other means to promote the development of cancer.

There are more than 5,300 compounds found in cigarette smoke including over 60 known carcinogens. At least 16 carcinogens are present in unburned tobacco.⁸ These carcinogens come from multiple chemical classes such as polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, aldehydes, volatile organic hydrocarbons and metals.^{4, 8} The carcinogens in cigarette smoke exert their effects through various genotoxic and/or non-genotoxic mechanisms.^{8, 9}

That carcinogens in cigarette smoke are absorbed into the blood and tissues of smokers has been confirmed by the measurement of these substances or modified versions (as biomarkers) in the breath, blood and urine. Measurement of urinary biomarkers is the most convenient method to quantify carcinogen exposure. However, many carcinogens found in cigarette smoke are also found in food and the general environment, so their metabolites are also detected in the urine of non-smokers. For example, PAHs are found in grilled foods and engine exhausts. The phenolic compounds, catechol and caffeic acid, are common dietary constituents. However, the N-nitrosamine, NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) is specific to tobacco. NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), a modified version of NNK, is the most discriminatory biomarker because the only source of its parent carcinogen (NNK) is tobacco products. NNAL is only detected in non-smokers if they have been exposed to secondhand tobacco smoke.⁶

PAHs and NNK are the major carcinogens involved in the development of lung cancer. In rodents, NNK exposure primarily causes the adenocarcinoma form of lung cancer. The concentration of NNK in tobacco smoke increased from 1959 to 1997 as the nitrate concentration in tobacco increased, and the risk of adenocarcinoma has also increased since the 1960s. The 2014 Surgeon General’s report suggested that ventilated filters and increased levels of tobacco-specific nitrosamines in cigarettes since the 1950s might have played a role in increasing this risk.² Other compounds from cigarette smoke that could also be involved in lung cancer include: 1,3-butadiene, ethylene oxide, ethyl carbamate, aldehydes, benzene and metals.

3.3.2 Genotoxic effects of cigarette smoke

3.3.2.1 DNA is the main target of genotoxic carcinogens

Genotoxic carcinogens change the sequence of a cell’s DNA. To understand the genotoxic actions of carcinogens, a brief introduction to DNA and cell biology is necessary. Each cell in the human body carries a copy of that person’s DNA. DNA is a long chain of repeated molecular units. The order of these units is referred to as the DNA sequence. Each cell in one person’s body should have an identical sequence, however, over time, changes in the DNA sequence accumulate. These changes can lead to problems, culminating in uncontrolled growth, which in some cases leads to cancer. Age is a risk factor for many cancers because the amount of DNA mutations increases as a person ages.

The DNA inside a human cell contains regions called genes. Most genes carry the instructions for making proteins, the building blocks of cells. There are tens of thousands of different types of proteins that make up human cells, each with differing functions. Groups of proteins work together to regulate specific cell processes. Pertinent to the formation of cancer are cellular process such as cell division (producing new cells as copies of the older ones), cell migration to new areas, programmed cell death (apoptosis: a natural process that is necessary to remove old or malfunctioning cells) and DNA repair (reducing the amount of DNA mutations). Alternatively, other types of genes carry instructions to make non-protein biological molecules, such as microRNAs. Some microRNAs also contribute to the formation of cancer when their sequence is changed by carcinogens.¹⁰

When mutations accumulate in the DNA sequence, they can change the proteins, microRNAs or other products produced by the genes. This sometimes leads to problems such as the loss-of-function or the gain-of-function for that gene product and its associated processes. A build-up of DNA mutations that disrupts processes such as cell division is the main underlying event leading to cancer—the out-of-control proliferation of cells. Some genes play a prominent role in the process of carcinogenesis. Mutations in these genes are more likely to cause cancer. Oncogenes (cancer promotors) are those in which mutations promote the formation of cancer. Tumour suppressor genes normally act to suppress the formation of cancer. Mutations that reduce the function of tumour suppressor genes are therefore promotors of cancer.

Cigarette smoke contains many carcinogens that have genotoxic activity.⁹ The molecular mechanisms by which these contribute to carcinogenesis are complex. There are numerous multi-step molecular pathways that share common features, leading to formation of cancer after exposure to tobacco or cigarette smoke. A generalised version of the main pathway is described below.

3.3.2.2 Activation of carcinogens to form DNA adducts

Exposure to cigarette smoke or unburned tobacco leads to the uptake of carcinogens into the body and into cells. Most tobacco or smoke carcinogens need to be converted into forms that can bind to DNA after uptake; a process called activation. Activation generally requires an enzyme, such as cytochrome P450. These enzymes are themselves increased in quantity by exposure to cigarette smoke. The activated carcinogens bind to DNA to form DNA adducts (carcinogen bound to DNA), which have the potential to cause changes (mutations) to the DNA sequence.⁶

There is overwhelming evidence that DNA adduct levels are higher in most tissues of smokers than non-smokers. The results of many biomarker studies demonstrate the potential for DNA sequence damage in smokers caused by the persistence of DNA adducts. This damage is consistent with the multiple gene changes found in lung and other cancers.¹¹

Cellular detoxification processes, which excrete carcinogen breakdown products in harmless forms, compete with the activation process. The balance between activation and detoxification varies between people. This may be due to the existence of multiple forms of the genes that code for the enzymes activating carcinogens. An example is the role of the enzyme cytochrome P450 2A13, which is produced primarily in the respiratory tract and participates in the activation of NNK. Some people have a variant of this enzyme with one-half to one-third the capacity to activate NNK. In a study of 724 lung cancer patients and 791 control subjects this variant was associated with a reduced risk of lung cancer.¹² Gene variants such as these may be part of the explanation for why some heavy smokers do not acquire lung cancer, but further research is required.

3.3.2.3 Conversion of DNA adducts to mutations

DNA adducts can cause DNA sequence alterations (mutations). The formation and accumulation of DNA sequence mutations is the underlying cause of cancers.

When a cell divides, a copy of the DNA is made by an enzyme called DNA polymerase. The DNA polymerase slides alone the DNA molecule making a second copy by inserting matching DNA subunits to ensure the second sequence is identical to the first. If the polymerase encounters a DNA adduct, the coping process can slow or halt. In some instances it continues, a process known as ‘translesion DNA synthesis’, which can result in the insertion of an incorrect DNA subunit. In other words, a DNA sequence mutation occurs. The accumulation of DNA mutations in oncogenes and tumour suppressor genes disrupts normal cell regulation, leading to out-of-control cell growth that is the basis of cancer. Over 22,000 mutations have been identified in small-cell lung cancer cells grown in the laboratory, indicating the considerable impact of the carcinogen cocktail present in cigarette smoke.¹¹

DNA mutations can change the function of genes and their protein or microRNA products. Inactivation of tumour-suppressor genes and activation of oncogenes that promote cancer are believed to contribute to the development of lung cancer. For example, 90% of patients with small-cell lung cancer, and 15% of patients with non-small cell lung cancer, have loss-of-function of the RB tumour-suppressor gene. The TP53 tumour-suppressor gene is mutated and inactivated in 70% of patients with small-cell lung cancer and 50% of those with non-small cell lung cancer. Activating mutations of the KRAS oncogene are seen in non-small cell lung cancers, but rarely in lung cancers of non-smokers.

DNA adducts are not mutations per se, and can be removed by various DNA repair mechanisms that protect human cells. Ideally, this happens before the cell division process when DNA polymerase copies the DNA. But the DNA repair process is sometimes insufficient to prevent the build-up of DNA sequence mutations that cause cancer. There is variability between people in their cells’ capacity for DNA repair. Researchers propose that this is due to the presence of different variants of DNA repair genes, contributing to differential susceptibility to tobacco-induced cancer.

3.3.3 Non-genotoxic effects of cigarette smoke

Non-genotoxic carcinogens contribute to the formation of cancer in ways that do not involve inducing DNA sequence mutations. Their mechanisms include oxidative stress, intercepting hormonal and signal transduction pathways, and epigenetics (non-mutation modifications to DNA that can change the amount of proteins produced from a gene). 

Some carcinogens from cigarette smoke bind to receptors on the surface of cells, leading to signals being transmitted into the cell. This can change cellular processes, separate to changes in DNA sequence.⁶ An example is nicotine and NNK binding to nicotinic acetlycholine receptors. These receptors are present in brain cells where they enable the addictive effects of nicotine. Aside from the brain, nicotinic acetylcholine receptors are found in various other sites including lung cells that come into contact with smoke. The binding of nicotine or NNK to these receptors promotes the survival and cell division of lung cancer cells. In normal lung cancer cells, nicotine binding to nicotinic acetlycholine receptors stimulates processes important to cancer formation such as increasing cell division and decreasing dependence on the extracellular matrix for survival. Activation of these receptors can also increase the formation of new blood vessels (a process called angiogenesis), supporting the growth of tumours. b-andrenergic receptors and ERBB receptors are also involved in signal transduction in response to tobacco carcinogens, with deleterious effects on cellular processes.⁶

Epigenetic changes are modifications to DNA that do not change the sequence of DNA subunits. Epigenetic changes often lead to an increase or decrease in the use of a gene, which can change cellular processes. These modifications are long-term changes that are preserved when a cell divides and are capable of being inherited. There are two common mechanisms for epigenetic modifications: DNA methylation and histone modification. During DNA methylation, small methyl molecules are fixed onto the DNA at specific sites called CpG islands. CpG islands often occur near the start of a gene, where modification can affect the amount of protein made from these genes. Histones are small proteins that act as spools for DNA to wind around. They play a role in determining the extent to which a gene is used. Modification of histone proteins can modify the use of a gene.

Exposure to tobacco smoke is implicated in the epigenetic modifications to DNA in genes that drive cancer. In lung cancer, over 50 genes are inactivated by methylation of CpG islands near the start of the gene.⁶ The processes regulated by these genes include cell division, DNA repair, programmed cell death, signal transduction and cell migration. An example of smoking linked to epigenetics is the methylation of the cell cycle regulation gene P16. Inactivation of P16 is one of the earliest events in the formation of lung cancer. Inactivation of P16 can be seen in lung specimens from one in five smokers but not from non-smokers. Data from rat experiments show that 94% of adenocarcinomas induced by NNK exhibited methylation at the P16 gene. Other genes such as RASSF1A are commonly methylated in various types of tumours in smokers.⁶

3.3.4 Loss of normal cell growth control mechanisms

DNA mutations and non-genotoxic changes induced by exposure to tobacco can disrupt the normal regulatory processes that control how cells behave. Many of the genes affected by cigarettes are cell cycle regulators. These genes control the tightly-regulated process by which cells divide to make copies of themselves. Uncontrolled cell division is a hallmark of most cancers.^{13, 14}

Programmed cell death (apoptosis) is a natural process for eliminating injured or unstable cells and preventing the malignant growth of cancer cells, without damaging the surrounding cells. Apoptosis is tightly regulated by a suite of interacting proteins.¹⁵ Apoptosis works against the formation of cancer by removing damaged cells that might seed the disease. DNA mutations that affect the regulators of apoptosis can lead to a reduction in the ability of apoptosis to prevent the development of cancer. Deregulation of apoptosis mechanisms is a characteristic of cancer cells.^{14, 16}

Genotoxic and non-genotoxic damage to cells from carcinogens changes other cell processes such as angiogenesis (formation of new blood vessels), dependence on the extracellular matrix for cell survival, contact inhibition (a process that stops cell division when they are too close to each other), metabolism, DNA repair processes and the ability of cells to migrate/invade into new areas of the body.¹⁴ Multiple changes in these processes are detected in cancerous cells.

Although much is known about smoking-associated carcinogenesis, particularly in relation to lung cancer, and to a lesser extent bladder cancer, there are still many unanswered questions. Further, the available data are unhelpful in terms of cancer prevention. Smoking cessation is the only proven strategy to reduce the damaging processes that lead to cancer.

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References

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