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.3 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, Sections 3.4 (lung cancer) and 3.5 (all 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.4 A compelling explanation of cancer causation needs to reflect these facts and the summary presented here discusses the issue of 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,5 and unless otherwise referenced the information has been sourced from this report.
The mechanisms by which cigarette smoking causes cancer are extremely complex, but nevertheless can be classified into two categories: genotoxic and non-genotoxic, or epigenetic.6 Genotoxicity means that the constituents of cigarette smoke damage the DNA of genes. This is believed to occur in a multi-step pathway: the carcinogens in cigarette smoke are activated by enzymes (which in turn have been activated, or induced, by cigarette smoke); the activated carcinogens bind to DNA to form compounds known as DNA adducts; DNA adducts disrupt normal DNA repair mechanisms causing gene mutations—inactivating tumour-suppressor genes and activating oncogenes (cancer promoters); and these gene mutations then disrupt normal cell growth control mechanisms, eventually resulting in cancer. The epigenetic pathway affects the last step of this pathway. The constituents of cigarette smoke alter the expression of genes (without affecting the underlying DNA), activating cell receptors, which then disrupt multiple processes involved in cell cycle regulation. These pathways are discussed in more detail below. Cigarette smoke also alters a range of immunologic functions and it is thought that these effects may promote tumours or act as co-carcinogenic stimuli.
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 pathogenic processes that lead to cancer.
3.3.1 Carcinogens in cigarette smoke
There are thousands of compounds in cigarette smoke, including more than 60 known carcinogens from multiple chemical classes, including polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, aldehydes, volatile organic hydrocarbons and metals.
The fact that carcinogens in cigarette smoke are absorbed into the bloodstream of smokers has been confirmed by the measurement of these substances or their metabolites (biomarkers) in 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 occur 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. Its metabolite, NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is therefore 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.
PAHs and NNK are the major carcinogens involved in the development of lung cancer. In rodents, NNK primarily produces the adenocarcinoma sub-type 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 also appears to have increased since the 1960s. The latest 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 this increased risk.7 Other compounds that could also be involved in lung cancer include: 1,3-butadiene, ethylene oxide, ethyl carbamate, aldehydes, benzene and metals.
3.3.2 Activation of carcinogens to form DNA adducts
The next major step in the carcinogenic process is binding of carcinogens to DNA to form the compounds known as DNA adducts. Most cigarette smoke carcinogens have to be converted to a form that can bind to DNA. This process is referred to as 'activation' and generally requires an enzyme, often one of the cytochrome P-450s (P-450s), to catalyse (speed) the process. These enzymes are 'induced' (essentially produced) by cigarette smoke.
Detoxification processes, which excrete carcinogen metabolites 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 (polymorphisms) of the genes that code for the enzymes that metabolise carcinogens. For example, the CYP2A13 gene, which is expressed primarily in the respiratory tract and participates in the activation of NNK, has a variant with one-half to one-third the capacity to activate NNK. In a study of about 700 lung cancer patients and almost 800 control subjects this variant was associated with a reduced risk of lung cancer. Genetic polymorphisms may be part of the explanation for differential susceptibility to cancer, but further research is required.
DNA adducts are central to the carcinogenic process. Measurement of DNA adducts is difficult because the amount of DNA available from routine procedures (such as bronchoscopy of the lung) is usually small, and adduct concentrations are typically low. Nevertheless, adducts of NNK and other carcinogens with deoxyguanosine and other DNA bases have been identified in human lung tissue, and DNA adduct levels are higher in most tissues of smokers than in corresponding tissues of non-smokers.
3.3.3 Conversion of DNA adducts to mutations
DNA adducts are not mutations per se, and can be removed by various DNA repair mechanisms that protect human cells. There is variability between people in this DNA repair capacity, and researchers hypothesise that this is also due to gene polymorphism, which leads to further differential susceptibility to tobacco-induced cancer.
When DNA repair is not completed before a normal DNA replication takes place, DNA synthesis 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 nucleotide (a component of RNA and DNA). In other words, a mutation occurs.
Inactivation of a number of tumour-suppressor genes, and activation of a number of oncogenes that promote cancer, are thought to be part of the development of lung cancer. These inactivations and activations occur as a consequence of mutations. 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, and the TP53 tumour-suppressor gene is mutated and inactivated in 70% of patients with small-cell lung cancer and 50% of non-small cell lung cancer patients. Activating mutations of the KRAS oncogene are seen in non-small cell lung cancers, but rarely in lung cancers of non-smokers.
Mutation is a complex process and subject. More than 22 000 mutations have been identified in a small-cell lung cancer cell line, highlighting the impact of the carcinogen cocktail in cigarette smoke.8
3.3.4 Loss of normal cell growth control mechanisms
Gene mutations can lead to a disruption of the normal regulation process for cell proliferation (growth) and apoptosis (death). The latter is a natural process for eliminating injured or unstable cells and it prevents the malignant growth of cancer cells. Deregulation of apoptosis mechanisms is a characteristic of cancer cells.
As mentioned above, in addition to adversely affecting normal cell growth regulation though gene mutations, components of cigarette smoke can disrupt cell control through epigenetic pathways, and this disruption can eventually result in cancer. For example, nicotinic acetylcholine receptors (nAChRs), which are the first line of contact between cells and cigarette smoke, are believed to be activated by NNK and by nicotine. This activation of nAChRs then promotes the processes required for the development of lung cancer, for example by stimulation of kinases that mediate cancer cell survival, by proliferation and resistance to chemotherapy and by promotion of angiogenesis (the growth of new blood vessels and a fundamental step in carcinogenesis).9
Genes can also be inactivated (silenced) and activated by hypermethylation, rather than chromosomal mutation. In lung cancer, more than 50 genes involved in regulating cell growth have been found to be affected by hypermethylation.
Relevant news and research
For recent news items and research on this topic, click
here.
(Last updated May 2019)
References
1. International Agency for Research on Cancer Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Volume 83. Lyon: International Agency for Research on Cancer, 2004. Available from: https://monographs.iarc.fr/ENG/Monographs/vol85/mono85.pdf
2. US Department of Health and Human Services. The health consequences of smoking: a report of the Surgeon General. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Available from: http://www.cdc.gov/tobacco/data_statistics/sgr/index.htm
3. Johnson K, Miller A, Collishaw N, Palmer J, Hammond S, Salmon A, et al. Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009). Tobacco Control 2011;Jan 20(1):e2. Available from: http://tobaccocontrol.bmj.com/content/early/2010/10/27/tc.2010.035931.full
4. Stewart B, Cotter T and Bishop J. Cancer and tobacco: its effects on individuals and populations. In: Robotin M, Olver I and Girgis A, eds. When cancer crosses disciplines. A physician's handbook, London: Imperial College Press, 2010.
5. US Department of Health and Human Services. How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease. A report of the US Surgeon General. Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010. Available from: http://www.surgeongeneral.gov/library/tobaccosmoke/report/index.html
6. Chen RJ, Chang LW, Lin P and Wang YJ. Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: an overview. Journal of Oncology 2011;2011:654931. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21559255
7. U.S. Department of Health and Human Services. The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014, Printed with corrections, January 2014. Available from: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf
8. Pleasance E, Stephens P, O'Meara S, McBride D, Meynert A, Jones D, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 2010;463(7278):184–90. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880489/pdf/ukmss-28042.pdf
9. Minna JD. Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer. The Journal of Clinical Investigation 2003;111(1):31–3. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151841/