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.
Tobacco History
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.
Smoking Gun
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.
K-ras
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.
p53
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 Connection
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.
Prevention
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
collar workers.
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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