Lung cancer is the leading cause of cancer deaths in the United States. Lung
cancer is almost entirely preventable, since the vast majority of cases are
due to cigarette smoking. Although tobacco has been used by American
Indians for 2,000 years and in western societies since the 16th century, cigarette
smoking is mainly a 20th century phenomenon.
Click on the buttons on the left to find out more about smoking and its link to lung cancer.
The tobacco plant Nicotiana rustica grows wild in the Americas. Its leaves were smoked, chewed, and brewed in teas by many Indian tribes. Tobacco smoking was used primarily in rituals, since it was believed that words and thoughts ascended to the Creator on the smoke. Hence, smoking the “peace pipe” was an oath to speak the truth in the presence of the Creator.
Columbus and other early explorers of the new world first observed tobacco smoking among Native Americans in the late 15th century. Sailors helped to popularize tobacco use in Spain and Portugal early in the 16th century. High-quality Nicotiana tobaccum was first planted in the Jamestown colony in 1613. Tobacco rapidly became a major cash crop in the colonies, especially in the South.
Tobacco was broadly introduced to Europe by Jean Nicot, for whom the genus Nicotiana is named. While ambassador to Portugal, in 1560 he sent tobacco to his queen, Catherine de Medici, as a remedy for her migraine headaches. Tobacco then gained the reputation as a wonder cure for everything from rabies to asthma – and even as a preventative of the plague. Queen Elizabeth’s royal explorer and dandy Sir Walter Raleigh popularized tobacco smoking for pleasure in the late 1600s.
During the 18th and 19th centuries, cigars, pipes, chew, and snuff were the major tobacco products. Cigarettes came to Britain with soldiers returning in 1856 from the Crimean War, where their French and Turkish allies had taught them to hand roll tobacco in thin papers. During the Civil War, Confederate soldiers were the first to receive a tobacco ration.
Cigarettes were first mass-produced in the U.S. in the 1880s by James Buchanan (“Buck”) Duke, of Durham, North Carolina. Duke also pioneered advertising when he began to package cigarettes with collectible trading cards. By the first decade of the 20th century, Duke had amassed 150 companies under the banner of the American Tobacco Company. This set the stage for the rapid acceleration of cigarette smoking in the U.S.
Lung Cancer Epidemic
About 163,000 Americans die each year from lung cancer. This is greater than deaths caused by the next four cancers combined.
Estimated US Cancer Deaths, 2005
Learn how cigarette smoking became a 20th century phenomenon. Click on the graph to highlight four periods when cigarette consumption showed great increases.
What was going on at each of these times? Roll over each period for an answer.
Now click on the periods when smoking declined.
What was going on at each of these times? Roll over each period for an answer.
Now let’s take a look at male deaths from lung cancer. Comparing the two graphs, approximately how many years do cancer deaths lag behind increases in cigarette consumption?
Now let’s add in the death rate for women. Roll over the female death rate for facts.
Phillip Dennis, M.D., Ph.D, National Naval Medical Center
The Tobacco epidemic is really responsible for 30% of all cancer deaths. The incidence of lung cancer in men in the U.S. has fallen since the Surgeon General's report first came out in 1964. The incidence of lung cancer in women has now plateaued and should be on its way down, if it follows the patterns of men. But for many years the incidence in women was increasing as the incidence in men was falling.
Killers in Smoke
With each puff, a cigarette smoker inhales over 60 known or suspected cancer-causing agents (carcinogens) – including polyaromatic hydrocarbons (PAHs), nitrosamines, and heavy metals.
Smoke moves with inhaled air down the respiratory tract – from the trachea to the bronchi, and then branching into ever-smaller bronchioles.
The bronchioles end in alveoli sacs where nicotine, carbon monoxide, and other gases in cigarette smoke are exchanged with the blood.
Smoke particles (soot) and gases are trapped in mucous that lines the cells of the respiratory tract. Hair-like projections (cilia) beat to sweep particles out of the lungs.
Smoke slows down and paralyzes cilia, impairing the lung’s ability to detoxify. Years of smoking eventually destroy cilia completely, and the lungs lose their sweeping effect. Then, cigarette particles become trapped in the mucus and cannot be expelled.
A thick, brownish tar builds up in the lungs, giving them a dark color. Carcinogens can then enter the lung cells and cause DNA damage. The damaged cells may eventually progress to lung cancer.
K-ras and p53 are the two genes most frequently mutated in smoking-related lung cancers. One tar component, benzo[a]pyrene, is specifically linked to known mutations in these genes – providing the equivalent of a "smoking gun" at a murder scene.
Within a lung cell, benzo[a]pyrene is converted to an epoxide.
The epoxide reacts readily with guanine (G) positions of the DNA helix.
If not corrected by the cell's DNA repair mechanism, this guanine “adduct” is misread as a thymine by the DNA polymerase that copies chromosomes during replication. Ultimately, the original G-C base pair may be replaced by a T-A base pair, a mutation called a transversion.
Cultured cells treated with benzo[a]pyrene show the same spectrum of G-T transversions as found in the k-ras and p53 genes of smokers. These mutational “hot spots” map well to the guanine binding sites of benzo[a]pyrene expoxide.
Benzo[a]pyrene can produce the major known activating mutation in the 12th codon of the K-ras gene.
Benzo[a]pyrene can also mutate three key positions in the p53 gene.
The protein produced by the K-ras gene is a tumor “activator.” K-ras is analogous to a car accelerator, because its overactivity contributes to tumor development. The K-ras protein resides on the inner side of the cell membrane, where it conducts growth signals from cell-surface receptors to the nucleus. This process is called signal transduction.
Signal transduction begins with the arrival of a growth factor at the cell surface, where it recognizes a specific receptor anchored in the cell membrane. The binding of the growth factor to its receptor conducts a growth signal into the cell interior.
The K-ras protein accepts the growth signal and, in turn, relays it to other molecules in the cytoplasm. Raf and other signal transducers are protein kinases, which activate other molecules by adding phosphate groups.
This signaling cascade culminates in the nucleus with the activation of Fos and Jun, two transcription factors that join together to initiate transcription of genes involved in cell replication.
Mutations in the K-ras gene result in a K-ras protein that is essentially stuck in an “on” position – perpetuating a signaling cascade in the absence of any real signal from a growth factor.
Mutations in the p53 gene are found in 70% of lung tumors, the highest rate for any cancer. The p53 protein is a tumor suppressor, analogous to car brakes, because its activity helps counter tumor development. P53 occupies a “checkpoint” in the cycle of cell division, where it “senses” DNA damage or mutations. The cell cycle is composed of four stages:
During the first Gap Phase (G1) the cell grows and replenishes its resources.
During S Phase (S) the cell synthesizes DNA in preparation for cell division.
During the second Gap Phase (G2) the cell synthesizes proteins and other cellular components needed for cell division.
During Mitosis Phase (M) the cell divides into two daughter cells.
P53 acts as a checkpoint into the critical Synthesis (S) and Mitosis (M) Phases. After receiving information from DNA repair systems, p53 can signal the cell to stop dividing, allowing time for a mutation to be repaired before it is passed on to daughter cells.
For example, p53 arrests the cell cycle, allowing time to repair G-T mutations induced by benzo[a]pyrene.
If the DNA damage is too great to repair, p53 can signal the cell to commit suicide by the process called apoptosis, or programmed cell death.
Mutations in p53 cause a loss of checkpoint control, allowing mutations and DNA damage to accumulate in a cell lineage.
Nicotine has long been known to be the habit-forming drug in cigarette smoke. However, recent research shows that nicotine also works with other components of smoke to promote cancer formation.
Phillip Dennis, M.D., Ph.D, National Naval Medical Center
So there are really three principle components of tobacco that have been identified that have adverse biological affects. Those include carcinogens, such as polyaromatic hydrocarbons and nitrosamines, as well as nicotine. The classic mechanism of lung carcinogenesis is based on the fact that carcinogens, when they are activated, end up causing DNA adducts and DNA damage.
Many of the nitrosamines that are carcinogens are actually nicotine metabolites. But nonetheless, they are present in cigarette smoke. So that when a person smokes, thereís exposure of epithelial cells to nicotine and nitrosamines. Nicotine and nitrosamines bind to nicotinic acetylcholine receptors, which have recently have been described on epithelial cells, which then transduce a signal to intracellular kinases that have profound cellular effects.
So the serine-threonine kinase Akt has become a very hot molecular target in cancer biology. It is a kinase that is activated in response to many types of stimuli. Once active, Akt will phosphorylate many downstream substrates. Over 50 have been described to date, and some of them are very key players in control of cell cycle – such as P27 and P21, apoptosis – such as Bad and Mdm2, and protein translation such as Mtor and Tsc2.
When Akt is activated by tobacco components in normal cells, it leads to the
increased proliferation and survival of these cells. In addition, active Akt
has been detected in the precursor to cancerous legions – bronchial
displasia – from smokers. So the cumulative evidence suggests that Akt
is an early and important target in lung cancer formation.
Akt likely plays a role in lung tumorigenesis through the following mechanism. A smoker is exposed to nicotine which, although we know it has biologic effects outside of addiction, is the addictive component. This leads to exposure to the carcinogens that cause DNA damage.
If DNA damage is not repaired, the cell has a crucial decision to make as to whether or not to undergo apoptosis. The role that Akt plays is probably in that crucial step. Because tobacco components activate Akt, which inhibits apoptosis, if Akt is active the apoptotic threshold is altered. And if apoptosis does not occur, it can lead to the accumulation of genetic changes – such as K-ras mutations, P53 mutations, etc – that are necessary for lung cancer formation.
Phillip Dennis, M.D., Ph.D. is head of the Signal Transduction section medical oncology at the
National Naval Medical Center. He is interested in how components of tobacco smoke activate signaling pathways that allow cancer cells to evade programmed cell death (apoptosis).
The implications of smoking cessation are profound. This is the most readily identifiable cause of lung cancer and is clearly something where we can intervene. In fact, in the state of California, they have been successful in decreasing the prevalence of smoking from 24% – which is on the national average – to about 12%. Aggressive anti-smoking campaigns that are comprehensive in their approach can do more to decrease the rate of lung cancer than any other intervention.The implications of smoking cessation are profound. This is the most readily identifiable cause of lung cancer and is clearly something where we can intervene. In fact, in the state of California, they have been successful in decreasing the prevalence of smoking from 24% – which is on the national average – to about 12%. Aggressive anti-smoking campaigns that are comprehensive in their approach can do more to decrease the rate of lung cancer than any other intervention.
Glorian Sorenson, Ph.D. is professor in the Harvard School of Public Health
and director of the Center for Community-Based Research at the Dana-Farber
Cancer Institute. She specializes in understanding how cancer interventions
can be tailored for different audiences and different social setting. Here
she describes an anti-smoking campaign that produced dramatic results in blue
So some of the large public service campaigns or public information campaigns
that have occurred over the last decade have clearly influenced more educated
sectors of the population to make changes in reducing tobacco use. But there
is still a chunk of the population – and we can think of
that in part as blue color workers and other workers – who haven't totally
reduced tobacco use in the same way. And actually if we also look at the rate
of the decline, the rate of the decline is also much slower. So we need to
think about what are ways we can particularly make programs relevant to these
workers or other parts of the population.
We started to hear from blue collar workers – and we were doing different types of programs – that they would tell us things like, 'Why should I quit smoking when I'm just exposed to all these hazardous substances in the workplace? It really doesn't make any difference for me if I quit smoking.' So that told us that one of the things we that need to step back and think about were some of the occupational hazards that blue collars were facing. So we designed a series of studies where we looked at what would happen if we actually integrated messages around occupational health and safety with messages around tobacco. One of the studies, just to give you an example of the study design, we actually recruited worksites to the study. We recruited worksites, particularly those that were likely to employ a large number of blue collar workers – so manufacturing sites. And we randomly assigned 15 worksites, half of them to a group that just received a standard health promotion kind of a program where they receive tobacco and other kinds of messages – focused only on lifestyle behaviors. In the other group, the worksites got both messages around their health behaviors, as well as around occupational health and safety.
So what we did was we randomly assigned the work sites, we surveyed the workers at the beginning to see what were the rates of tobacco use or other health behaviors, we offered the programs within all of the sites, and then at the end – after about 18 months – we did another survey to look at changes in health behaviors. And then compared that between the two groups, the group only getting the health promotion and the group getting health promotion and health protection. And what we found was that for blue-collar workers in the integrated group, they were twice as likely to quit smoking as blue-collar workers in the group that got only the health promotion piece.
There were no differences between groups in the white-collar workers, but we find that white collar workers, in general, quit at greater rates than blue-collar workers. But in this case we found that for those blue collar workers in the group getting the integrated message, they actually quit smoking at the same rate as the white-collar workers so one of the things we're taking away from that is that it's really important that we think about those occupational hazards as we're thinking about work-site health promotion. But it also tells us on a more global level that we need to understand some of the aspects of people's context of their day-to-day lives that would make interventions more relevant to them, and would address their health concerns in a holistic manner.
Tobacco use in the population overall is probably around 20-21% right now in terms of prevalence. So that means about 21% of the adult population overall uses tobacco. But if we look at how that varies across the population, we'll see huge differences. For some blue collar workers we would see prevalence rates of 35-40 percent, compared to maybe in some white collar or more educated populations of maybe under 10 percent. So there are very large differences, and that means that as we develop approaches to tobacco use cessation, we need to think about the audiences where messages around tobacco use have been least successful.
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