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Why are only few cigarette smokers prone to cancer?

Why are only few cigarette smokers prone to cancer?


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It's tacit that only a few populace of smokers get cancer. What spares the others from it or what specifically cause cancer in those populace? See this Washington Post Article


Cigarette smokers are most certainly prone to cancer. See Cecil Medicine, Chapter 183, on the epidemiology of cancer, exposure to tobacco is the most important environmental risk factor for cancer development, at least in the US:

Exposure to tobacco is the single largest cause of cancer in the United States… All forms of tobacco can cause cancer. Cigarette smoking causes cancer of the lip, oral cavity, nasal cavity, paranasal sinuses, pharynx (nasal, oral, and hypopharnyx), larynx, lung, esophagus (squamous cell and adenocarcinoma), stomach, colorectum, pancreas, liver, kidney (adenocarcinoma and renal pelvis), urinary bladder, uterine cervix, and myeloid leukemia.

Cancer may be identified or the cause of death in fewer smokers than might be expected, though, because smoking is an even greater risk factor for cardiovascular disease, and death due to cardiovascular disease.

Cancer is an unlikely phenomenon in an individual cell, but becomes more likely at the organism level, and even more likely over time. Though tobacco may be the most important environmental risk factor for cancer, age is actually a stronger predictor of cancer (see again, Cecil Chapter 183. Autopsy studies give us a quite remarkable example, this one shows incidental prostate cancer in nearly 60% of men over 80 who died from other causes. That figure is not out of the ordinary. Live long enough and you are likely to develop cancer.

Death due to heart disease may account for the lower than expected rates of cancer diagnoses and deaths in smokers. Nothing prevents cancer as well as dying from something else. And as discussed in the blog in the Washington Post you linked to, up to 2/3 of smokers die from smoking related causes


Why People Start Smoking and Why It’s Hard to Stop

Most people who smoke started smoking when they were teenagers. Those who have friends and/or parents who smoke are more likely to start smoking than those who don’t. Some teenagers say that they “just wanted to try it,” or they thought it was “cool” to smoke.

The tobacco industry’s ads, price breaks, and other promotions for its products are a big influence in our society. The tobacco industry spends billions of dollars each year to create and market ads that show smoking as exciting, glamorous, and safe. Tobacco use is also shown in video games, online, and on TV. And movies showing people smoking are another big influence. Studies show that young people who see smoking in movies are more likely to start smoking.

A newer influence on tobacco use is the e-cigarette and other high-tech, fashionable electronic “vaping” devices. Often wrongly seen as harmless, and easier to get and use than traditional tobacco products, these devices are a way for new users to learn how to inhale and become addicted to nicotine, which can prepare them for smoking.


Inhaling from just 1 cigarette can lead to nicotine addiction

WORCESTER, Mass. -- A new study published in the Archives of Pediatric and Adolescent Medicine shows that 10 percent of youth who become hooked on cigarettes are addicted within two days of first inhaling from a cigarette, and 25 percent are addicted within a month. The study found that adolescents who smoke even just a few cigarettes per month suffer withdrawal symptoms when deprived of nicotine, a startling finding that is contrary to long-held beliefs that only people with established smoking habits of at least five cigarettes per day experience such symptoms.

The study monitored 1,246 sixth-grade students in six Massachusetts communities over four years. Students were interviewed frequently about smoking and symptoms of addiction, such as difficulty quitting, strong urges to smoke, or nicotine withdrawal symptoms such as cravings, restlessness, irritability, and trouble concentrating. Of those who were hooked, half were already addicted by the time they were smoking seven cigarettes per month. As amazing as it may seem, some youth find they are unable to quit smoking after just a few cigarettes. This confirms an earlier study by the same researchers.

Recent research has revealed that the nicotine from one cigarette is enough to saturate the nicotine receptors in the human brain. "Laboratory experiments confirm that nicotine alters the structure and function of the brain within a day of the very first dose. In humans, nicotine-induced alterations in the brain can trigger addiction with the first cigarette," commented Joseph R. DiFranza, MD, professor of family medicine & community health at the University of Massachusetts Medical School and leader of the UMMS research team. "Nobody expects to get addicted from smoking one cigarette." Many smokers struggle for a lifetime trying to overcome nicotine addiction. The National Institutes of Health estimates that as many as 6.4 million children who are living today will die prematurely as adults because they began to smoke cigarettes during adolescence.

"While smoking one cigarette will keep withdrawal symptoms away for less than an hour in long-time smokers, novice smokers find that one cigarette suppresses withdrawal for weeks at a time," explained Dr. DiFranza. "One dose of nicotine affects brain function long after the nicotine is gone from the body. The important lesson here is that youth have all the same symptoms of nicotine addiction as adults do, even though they may be smoking only a few cigarettes per month."

Symptoms of nicotine addiction can appear when youth are smoking as little as one cigarette per month. At first, one cigarette will relieve the craving produced by nicotine withdrawal for weeks, but as tolerance to nicotine builds, the smoker finds that he or she must smoke ever more frequently to cope with withdrawal.

According to DiFranza, the addiction-related changes in the brain caused by nicotine are permanent and remain years after a smoker has quit. This explains why one cigarette can trigger an immediate relapse in an ex-smoker. It also explains why an ex-smoker who relapses after many years of abstinence cannot keep the craving away by smoking one cigarette per month. Unlike the newly addicted novice smoker, a newly relapsed smoker must smoke several cigarettes each day to cope with the craving.

The study was supported by the National Institute on Drug Abuse and appears in the July issue of the Archives of Pediatric and Adolescent Medicine. According to the National Institutes of Health, smoking remains the leading preventable cause of death in the United States, accounting for approximately 440,000 deaths annually.

DiFranza worked on this study with UMMS colleagues Judith K. Ockene, PhD, Judith A. Savageau, MPH, Kenneth Fletcher, PhD, Lori Pbert, PhD, Jennifer Hazelton, BA, Karen Friedman, BA, Gretchen Dussault, BA, and Connie Wood, MSW Jennifer O'Loughlin, PhD, of McGill University Ann D. McNeill, PhD, of St. George's Hospital Medical School at the University of London and Robert J. Wellman of both UMMS and Fitchburg State College.

About the University of Massachusetts Medical School

The University of Massachusetts Medical School is one of five campuses of the University system and one of the fastest growing academic health centers in the country, attracting more than $174 million in research funding annually. It encompasses the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, and perennially listed among the top ten percent in the annual US News & World Report ranking of primary care medical schools. The mission of UMass Medical School is to serve the people of the Commonwealth through national distinction in health sciences education, research and public service. It is the academic partner of UMass Memorial Health Care. Go to www.umassmed.edu for more information.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


How smoking tobacco damages your lungs

Smoking damages the airways and small air sacs in your lungs. This damage starts soon after someone starts smoking, and lung function continues to worsen as long as the person smokes. Still, it may take years for the problem to become noticeable enough for lung disease to be diagnosed.

Smoke damage in the lungs can lead to serious long-term lung diseases such as chronic obstructive pulmonary disease (COPD). Smoking can also increase the risk of lung infections such as pneumonia and tuberculosis, and it can worsen some existing lung diseases, such as asthma.

COPD, which is one of the leading causes of death in the United States, includes both chronic bronchitis and emphysema (discussed below). Most people with COPD have both of these conditions, but the severity of each of them varies from person to person.

In COPD, damage to the small airways in the lungs makes it hard for the lungs to get oxygen to the rest of the body.

Smoking is by far the most common cause of COPD. The risk goes up the more you smoke and the longer you smoke.

Some of the early signs and symptoms of COPD can include noises in the chest (such as wheezing, rattling, or whistling), shortness of breath when active, and coughing up mucus (phlegm). Over time, COPD can make it hard to breathe at rest as well, sometimes even when a person is getting oxygen through a mask or nasal tube.

COPD tends to get worse over time, especially if a person continues to smoke. There is no cure for COPD, although some medicines might help with symptoms.

Chronic bronchitis

Chronic bronchitis is a common problem in people who smoke for a long time. In this disease, the airways make too much mucus, forcing the person to try to cough it out. The airways become inflamed (swollen), and the cough becomes chronic (long-lasting). The symptoms can get better at times, but the cough keeps coming back. Over time, the airways can get blocked by scar tissue and mucus, which can lead to bad lung infections (pneumonia).

There’s no cure for chronic bronchitis, but quitting smoking can help keep symptoms under control and help keep the damage from getting worse.

Emphysema

In emphysema, the walls between the tiny air sacs in the lungs break down, which creates larger but fewer sacs. This lowers the amount of oxygen reaching the blood. Over time, these sacs can break down to the point where a person with emphysema might struggle to get enough air, even when at rest.

People with emphysema are at risk for many other problems linked to weak lung function, including pneumonia. In later stages of the disease, patients often need an oxygen mask or tube to help them breathe.

Emphysema cannot be cured, but it can be treated and slowed down if the person stops smoking.

Why do people who smoke have “smoker’s cough?”

Tobacco smoke has many chemicals and particles that can irritate the upper airways and the lungs. When a person inhales these substances, the body tries to get rid of them by making mucus and causing a cough.

The early morning cough common among people who smoke happens for many reasons. Normally, tiny hair-like structures (called cilia) in the airways help sweep harmful material out of the lungs. But tobacco smoke slows this sweeping action, so some of the mucus and particles in the smoke stay in the lungs and airways. While the person sleeps (and doesn’t smoke), some cilia recover and start working again. After waking up, the person coughs because the lungs are trying to clear away the irritants and mucus that built up from the day before.

So-called “smoker’s cough” can be an early sign of COPD.


No safe level of smoking: Even low-intensity smokers are at increased risk of earlier death

People who consistently smoked an average of less than one cigarette per day over their lifetime had a 64 percent higher risk of earlier death than never smokers, and those who smoked between one and 10 cigarettes a day had an 87 percent higher risk of earlier death than never smokers, according to a new study from researchers at the National Cancer Institute (NCI). Risks were lower among former low-intensity smokers compared to those who were still smokers, and risk fell with earlier age at quitting. The results of the study were reported Dec. 5, 2016, in JAMA Internal Medicine. NCI is part of the National Institutes of Health.

“. smoking even a small number of cigarettes per day has substantial negative health effects. ”

Maki Inoue-Choi, Ph.D., NCI, Division of Cancer Epidemiology and Genetics

When researchers looked at specific causes of death among study participants, a particularly strong association was observed for lung cancer mortality. Those who consistently averaged less than one cigarette per day over their lifetime had nine times the risk of dying from lung cancer than never smokers. Among people who smoked between one and 10 cigarettes per day, the risk of dying from lung cancer was nearly 12 times higher than that of never smokers.

The researchers looked at risk of death from respiratory disease, such as emphysema, as well as the risk of death from cardiovascular disease. People who smoked between one and 10 cigarettes a day had over six times the risk of dying from respiratory diseases than never smokers and about one and half times the risk of dying of cardiovascular disease than never smokers.

Smoking has many harmful effects on health, which have been detailed in numerous studies since the U.S. Surgeon General’s 1964 report linking smoking to lung cancer. The health effects of consistent low-intensity smoking, however, have not been well studied and many smokers believe that low-intensity smoking does not affect their health.

To better understand the effects of low-intensity smoking on mortality from all causes and for specific causes of death, the scientists analyzed data on over 290,000 adults in the NIH-AARP Diet and Health Study. Low-intensity smoking was defined as 10 or fewer cigarettes per day. All participants were age 59 to age 82 at the start of the study.

Participants were asked about their smoking behaviors during nine periods across their lives, beginning with before they reached their 15 th birthday until after they reached the age of 70 (for the older participants). Among current smokers, 159 reported smoking less than one cigarette per day consistently throughout the years that they smoked nearly 1,500 reported smoking between one and 10 cigarettes per day.

The study relied on people recalling their smoking history over many decades, which introduced a degree of uncertainty into the findings. Also, despite the large number of people surveyed, the number of consistent low-intensity smokers was relatively small.

Another limitation of the study is that the participants were mostly white and in their 60s and 70s, so the smoking patterns collected in the study reflect only a particular set of age groups in the United States. Future studies among younger populations and other racial and ethnic groups are needed, particularly as low-intensity smoking has historically been more common among racial and ethnic minorities in the US. The study also lacked detailed information about usage patterns among participants who reported smoking less than one cigarette per day. Hence, the researchers could not compare the effects of smoking every other day, every few days, or weekly, for example.


Lung Cancer Screening

In the past, there were not many effective screening tests for lung cancer. People had to rely on the identification of the early symptoms in the hope of spotting the disease in the initial and most treatable stages.

However, since nearly half of people with lung cancer are diagnosed in the advanced stages, general knowledge may not be enough to keep you safe.

For people who are at an increased risk of lung cancer, advanced computed tomography (CT) screening can improve the chances of early detection and, when used appropriately, reduce the risk of mortality by 20%.  

According to the U.S. Preventive Services Task Force, people who should have yearly CT screenings for lung cancer are those who:

  • Are between the ages of 50 and 80
  • Have a 20 pack-year history of smoking
  • Currently smoke or have quit in the past 15 years
  • Are in reasonable physical condition such that surgery can be performed if a tumor is found

There are others who may benefit from screening as well. For example, anyone exposed to cancer-causing substances in the workplace, such as radon or aerosolized benzene, may reasonably request CT screening.

If you feel that you are at an increased risk of cancer and require screening, talk to your doctor.


Cancer: a disease of our genes

So, why is it we’re more likely to get cancer as we get older? Cancer is a disease caused by errors in our genes – the DNA code in our cells that provides the blueprints for all cell functions. These errors arise for a number of reasons.

Chemical carcinogens and radiation are two factors many immediately think of, and can be major players in some cancers. Chemical carcinogens in cigarette smoke contributing to lung cancer and UV radiation contributing to melanoma are two obvious examples.

We can also inherit some genetic errors. For example, defective BRCA genes are passed down in some families and contribute to a number of cancers, including those of the breast and ovary. Some viruses can also contribute to cancer, such as the human papillomavirus (HPV) with cervical cancer.

Another main reason for genetic errors arising, however, comes from normal biology. The body is made up of many trillions of individual cells, and in most cases these individual cells have a defined lifespan.

As these cells die they’re replaced by new cells that arise from the division of another cell into two a process that requires replication of all of the cell’s DNA.

Despite this DNA replication being highly controlled and very accurate, the sheer number of times it is performed in the lifespan of a person (estimated to be 10,000 trillion times!) means the introduction of a significant number of errors into the DNA of some of our cells from this fundamental process is inevitable.

Longer life means more cancer. from www.shutterstock.com


G Marks the Spot: Where Mutations Happen

By studying the DNA-carcinogen adducts at the atomic scale, scientists have learned that they preferentially form at guanine bases in DNA. Normally, a guanine base pairs with a cytosine base in the DNA helix. But when DNA with an adduct is replicated, the enzymes that do the copying tend to put an adenine base opposite this guanine, rather than the usual cytosine. This leads to what’s called a G-to-T transversion.

You can think of a transversion as a kind of reading error. Say a speck of dirt fell on the page of the book you were reading and made an F look like a P. Instead of “Fine,” you read “Pine.” This changes the meaning of the sentence.

According to Ken Marians, a DNA replication expert at SKI, an abundance of G-to-T tranversions in DNA is a hallmark of smoking-induced damage and has been dubbed the “smoking signature.”

Different types of environmental factors cause different types of mutations. Ultraviolet light, for example, produces CC to TT mutations. These distinct changes may help identify which treatments are suited to a particular person.

Among the genes commonly mutated in lung cancer is TP53, which makes a protein called a tumor suppressor. These proteins provide a built-in defense against cancer.

Scientists have shown that the sites of mutation in the TP53 gene found mostly commonly in people with lung cancer match the sites of adduct formation. This is strong evidence that the DNA adducts are the source of mutations in smoking-related cancers.

Carcinogens in cigarette smoke cause mispairing of a G base with an A base in DNA. When this DNA is replicated, the new copy has a T where the old copy had a G, called a G-to-T transversion. Illustration by Wenjing Wu.


Cancer Interception

A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res 4(6) 787–92. ©2011 AACR.

Cancer interception is the active way of combating cancer at earlier and earlier stages. Most people not working in or very familiar with the field usually think that cancer “prevention” is somewhat passive, such as smoking avoidance to prevent getting lung cancer, which is an example of primary prevention. Although this category is crucially important, other approaches are needed as well. This need is emphasized by the startling fact that now the majority of new lung cancers develop in former smokers where preventive agents appear to be more active (1). The growing science and knowledge of cancer biology and treatment are showing us ways to intercept cancers by new, active approaches. The term “cancer interception” captures this idea: to actively intercept a cancer development process before the damage is done, that is, before the full-blown advanced tumor presents in the clinic (Fig. 1). A great challenge for medicine is to let people know that the development of cancers, like heart disease, can be intercepted with risk-reducing agents, in the same way that cancers can be treated with drugs or that cardiovascular disease (CVD) can be intercepted with antihypertensive and other risk-reducing drugs.

Cancer interception. As in a game of American football, the Cancer touchdown (top) can be prevented by interception (bottom), thus preserving good health. Intercepting cancer can be accomplished by various means including oral small molecules, vaccines, and physical activity.

Intercepting, or actively preventing, cancer has been a hard sell heretofore, including even among people prone to exploring it for their personal health. Even educated, at-risk people have trouble with adherence to risk reduction for example, adherence to established effective breast cancer risk–reducing agents has proven challenging despite active adherence promotion. Yet, although confronting similar challenges, risk reduction in other settings such as CVD and osteoporosis has met with widespread acceptance.

Why has pharmacologic CVD risk reduction become so widely accepted, whereas pharmacologic cancer risk reduction has not? One proposed reason is that CVD risk reduction treats measurable conditions—notably, hypertension and high cholesterol levels—that patients can follow to assess effectiveness. Cancer interception or risk reduction actually also has at least one good example of a marker of success. Aspirin can reduce the number of detectable colorectal adenomas (the measurable condition) and has been shown to reduce colorectal cancer mortality and incidence in long-term follow-up of randomized controlled CVD trials aspirin also is associated with the reduced mortality of several other common cancers (2, 3). In this case, surgical control of colorectal adenomas has established this lesion as a biomarker of cancer risk and mortality reduction (4). Another proposed obstacle to public acceptance of cancer risk reduction is the risk of toxic effects. This concern may be allayed, in part, by a new study of celecoxib and other nonsteroidal anti-inflammatory drugs (NSAID), which, like aspirin, were shown to be active in intercepting colorectal neoplasia but, unlike aspirin, to also produce adverse CV effects. The new data indicate that low-baseline CVD risk or low-baseline C-reactive protein level eliminates the risk of NSAID-associated CVD toxicity (5). This example, furthermore, emphasizes another important concept: More “personalized” cancer interception may be the most effective. It is notable that CVD risk reduction with antihypertensive agents also has risks of substantial toxicity. Nevertheless, these proposed reasons have a sound basis and speak to a lack of effective public education about the parallels of cancer risk reduction with CVD risk reduction, and the need to remedy this lack (6).

Cancer interception has never been more desirable or necessary. In the United States, for example, 44% of men and 38% of women will develop cancer in their lifetimes. Eighty-four percent of all cases are diagnosed after age 60 31% of all cases are diagnosed after age 80. The population is aging, and an increased fraction of the population in the United States and world is reaching cancer-prone ages. Early detection increases cancer diagnosis rates. Treatment has improved, increasing the life spans of cancer patients survivors are at increased cancer risk. These factors all point to a significantly increasing cancer burden that can only be mitigated by a double-pronged approach: interception as well as treatment.

Advances in cancer research have created an optimal time to discover and implement cancer interception. Lessons can be learned from risk reduction drug development in the CVD setting (7). The first advances in CVD prevention derived from (a) antihypertensive agents in treating patients with high-risk severe hypertension (diastolic blood pressure: 115–129) or with class III/IV heart failure, (b) statins in treating patients with prior myocardial infarction (MI) and very high LDL (low-density lipoprotein) cholesterol, and (c) aspirin in treating patients with prior MI or stroke. All these therapies were effective in advanced disease and subsequently were tried and became standard in lower risk settings of CVD prevention (7).

This reverse migration (from therapy and established disease to intercepting disease before it becomes established Fig. 2 refs. 8–10) is illustrated in several settings. Both selective estrogen receptor modulators (SERM) and aromatase inhibitors were pursued for treating advanced breast cancer before showing activity in preventing it. SERMs were developed as a result of the early discoveries of the ER and its role in breast cancer (11). These agents first proved active in advanced cancer (30% activity in ER-positive tumors), then worked back through the adjuvant setting (resected ER-positive early breast cancer, where they reduced recurrence by 50%, ER-negative recurrence by 6%), and next worked back to effective prevention with the SERM raloxifene in moderate-risk women with no cancer history (50% prevention overall, 80% prevention of ER-positive breast cancer, and ineffective in preventing ER-negative disease refs. 12, 13). Androgen suppression therapies in prostate cancer also have reverse migrated from metastatic to locally advanced (14) to interception of disease (15, 16). Breast research has also shown that molecular subtypes, which are intensively studied in invasive breast cancer biology and treatment, are now known to exist in premalignant breast disease (17) and are becoming increasingly clear in pre-premalignant cells, driven in large part by cellular stress and molecular heterogeneity (18, 19). This work has major implications for risk profiles and targeted interception. Human papilloma virus 16 (HPV16) was linked to cervical cancer (20), leading to the development of an active HPV16 vaccine (21, 22), followed by the development of bivalent and quadravalent HPV vaccines for standard interception of cervical premalignancy and cancer. More recently HPV, particularly HPV16, has been linked to oropharyngeal cancer, and the reverse migration development of vaccination to intercept oropharyngeal cancer is now in progress (23). Reverse migration in myeloma has involved lenalidomide, which is an immunomodulator capable of enhancing immune cell function via activation of T cells and natural killer cells and via increased expression of death effector molecules. Standard-dose lenalidomide plus high-dose dexamethasone produced an approximately 60% response rate (and median time to progression of 12 months) in advanced, relapsed multiple myeloma (24). A very recent phase III trial randomly assigned patients with the precursor stage, high-risk smoldering multiple myeloma to no treatment (the standard approach for this disease) versus treatment with standard-dose lenalidomide plus low-dose dexamethasone induction followed by low-dose lenalidomide alone. Progression to clinically active myeloma occurred in 8% (5 of 60) of lenalidomide-treated patients versus 46% (28 of 61) of no-treatment/control patients after 22 months of median follow-up median time to progression was 25 months (no treatment) versus not reached (treatment HR = 8.0, P < 0.0001 ref. 25). Recent study of agents targeting interleukin 6 is showing great promise in this setting.

Advances in the biology and interception of premalignancy derive from advances in the biology and therapy of cancer. The color saturation at the right-hand side of the horizontal arrows reflects the greater body of work in cancer biology and therapy. The reverse migration arrow reflects the movement of small molecules and other agents from therapy to interception. The cancer-hallmarks diagram (9) at the right shows three examples of hallmarks that were originally targeted in malignant cancer by small molecules currently on the path of reverse migration toward interception (see text). Molecular techniques (bottom ref. 10) that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. In particular, next-generation sequencing platforms, an emerging technology that has been used to profile the epigenome and transcriptome in cancer tissue, are now being applied to the study of premalignant cells (RNA-seq, bottom right ref. 46). RPPA, reverse-phase protein array CNV, copy number variance ChIP-seq, chromatin immunoprecipitation sequencing. (The cancer-hallmarks diagram in this figure was adapted with permission from Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011144:646–74.)

The breast provides another promising reverse migration in the form of synthetic lethality, an emerging approach of personalized, targeted therapy and, also, interception. PARP inhibitors induced therapeutic synthetic lethality in BRCA mutation carriers with advanced breast (26) and ovarian cancer and have since moved into early clinical testing for breast cancer interception (27). The development of this approach includes a phase II therapy trial of the PARP inhibitor olaparib (competitive inhibitor of PARP1 and PARP2), which produced a response rate of 41% in advanced breast cancer patients with germ line BRCA1 or BRCA2 mutations. Synthetic lethality with other agents [TNF-related apoptosis-inducing ligand (TRAIL) plus a Smac/DIABLO mimic] has moved into preclinical testing for the interception of colorectal and lung neoplasia (28, 29). This synthetic lethality approach targets APC and KRAS mutations, which occur in invasive and preinvasive disease, respectively (30).

Reverse migration is also exemplified very well by the biology of hedgehog signaling in basal cell cancer. Basal cell skin cancer, the most common cancer in humans, results largely from mutations in hedgehog pathway genes, including the protein patched homolog 1 (PTCH1) gene, which constitutively activates smoothened (SMO) during progression to basal cell cancer. The oral, highly specific small-molecule SMO inhibitor GDC-0449 first produced remarkable clinical responses (response rate of 50%) in advanced metastatic basal cell carcinoma (31) and then nearly completely suppressed basal cell lesions (P < 0.001) in a very recent double-blind, placebo-controlled randomized prevention trial in 41 very high-risk Gorlin syndrome patients, who have a germ line PTCH1 mutation patients were randomly assigned in a drug-to-placebo ratio of 2 to 1 (32). GDC-0449 also reduced the downstream hedgehog signaling target Gli1 mRNA levels by 200-fold. Despite the small number of patients, this trial was very robust because of its extremely high-risk setting it also is an excellent example of taking personalized cancer therapy back into interception (33). Even in this robust, positive trial, most lesions recurred after stopping therapy, underscoring the importance of understanding drug resistance mechanisms. Recent study suggesting cross-talk between hedgehog and insulin-like growth factor pathways potentially will advance our understanding of resistance in this setting and will contribute to the identification of targeted agents for overcoming it (34).

Last, like so much in cancer biology, telomere maintenance or dysfunction (which is caused by inadequate maintenance of telomeres, causing them to shorten) is a double-edged sword with distinct, context-specific effects (35, 36). For example, telomere maintenance in normal cells protects against genomic instability that can lead to cancer or other aging-related diseases whereas, once the full hallmarks of cancer develop (9), telomere maintenance can enable the advanced malignant cells to keep replicating. Telomere shortness in normal cells (with its concomitant potential for loss of genome protection) is a measurable risk factor for the clinical development of cancer (37). That rare inherited genetic mutations in genes causing telomere shortness are clearly linked to cancer has been known for a while (38, 39). It was not known until recently, however, whether common single-nucleotide polymorphisms (SNP) associated with cancer also are associated with telomere changes. Very recent work was first in showing that the association between a common SNP in the general population and bladder cancer is statistically significantly mediated in part by telomere shortening (40) other factors contribute to the risk of bladder cancer as well. The influence of telomere maintenance or dysfunction in premalignant or normal-appearing but molecularly altered precancerous cells is less clear. In a normal cell, telomere dysfunction causes cells to senesce (i.e., stop proliferating), thus intercepting any potential trajectory toward cancer development. But, such senescent cells secrete tumor-promoting factors and thus may promote cancer progression in neighboring cells (41). In a cell with molecular damage (even a normal-appearing cell), telomere dysfunction can launch the cell toward carcinogenesis. The predisposing damage may come from cellular stress related to obesity, inflammation, smoking, and psychosocial factors (42), all of which are associated with telomere shortness and dysfunction. A recent study of psychosocial factors has shown that psychological stress increases cancer progression in the breast and ovaries, but it is unclear if it also increases cancer risk (43). A study of the influence of psychosocial stress on molecular changes in metastasis identified molecular targets that could lead to the interception of metastasis development for example, such a target was suggested by recent work showing the mechanistic link between adrenergic stress and focal adhesion kinase (FAK) activation (which protects cells from anoikis), supporting the potential of β-2 adrenergic receptor blockers to intercept metastasis (44). Although clinical therapy trials in advanced cancers are only just beginning to target telomerase activity, there are many other genes involved in regulation of telomere function and many cellular pathways that can indirectly affect it (e.g., DNA repair pathways). There are a number of telomere maintenance genes encoding telomerase components (e.g., hTERT and hTERC) and telomere-protective proteins (e.g., TIN2, TRF1, and TRF2) which may lead to the discovery of targets for cancer interception (45).

Advances over the next few years in cancer research that will continue to feed into cancer interception, for example, for profiling premalignant cells, will arise largely from rapidly emerging next-generation sequencing platforms (Fig. 2). Elsewhere in this issue of the journal, Beane and colleagues show the potential impact of transcriptome sequencing (RNA-seq) on developing novel insights into the early molecular events in airway epithelial cells that may lead to the development of lung cancer among smokers (46). This group previously used microarray technology to globally profile the mRNA changes associated with tobacco smoke exposure (47, 48) and to identify a gene expression signature in the bronchial airway that can serve as a sensitive and specific biomarker for the early detection of lung cancer (49). These alterations in airway gene expression may precede the development of lung cancer and can potentially be reversed by preventive strategies (50). Using the next-generation sequencing platform RNA-seq, this group has now uncovered novel coding and noncoding RNAs, whose expression is altered in the airway in response to smoking and lung cancer and which microarrays did not interrogate or find to be significantly altered (46). In addition to their potential for providing novel insights into the molecular field of injury associated with tobacco smoke exposure, coding and noncoding transcripts uncovered by RNA-seq may function as biomarkers of lung cancer risk and as novel targets for prevention.

Although treating or even curing cancer is often, understandably, at the forefront of people's minds, cancer will never be brought under control unless the other side of the equation is addressed: intercepting, or preventing, it (Fig. 1). This is not impossible. Just from smoking control efforts alone, countless cancers have been prevented, and interception can be accomplished with diet and exercise (51) interventions as well, with effects of exercise possibly mediated in part by effects on telomere maintenance (52). Prevention is clearly more cost-effective—counting at least human costs—than treatment. The ability to intercept cancers at earlier and earlier stages, which is arising from the rapidly increasing armamentarium of emerging technologies and therapies, is predicted to further reduce the burden of cancer on the health and well being of the public.


Why Smoking Is Linked With a Higher Risk of Aneurysms, and How to Kick the Habit

In the nearly 40 years since she had been lighting up, 57-year-old Elaine Duff has made repeated attempts to quit smoking, from using the nicotine patch to taking prescription medication. Duff, of Newton, North Carolina, never saw success in her efforts and eventually gave up, relying on the false hope that she, like some of her other, older family members, would remain healthy despite the habit.

But in 2013, Duff’s perspective changed when a sudden headache progressed to body-wide debilitation while in her home cellar. As she tried to make her way up the stairs, she fainted. When Duff woke 30 minutes later, she managed to make it up the stairs with the help of her dog Trouble, a black Labrador retriever, and call 911.

When paramedics arrived, Duff was transported to the hospital and then airlifted to Wake Forest Baptist Health in Winston-Salem, where doctors diagnosed her with a cerebral aneurysm and a subarachnoid hemorrhage (brain bleed). Although the aneurysm was 5 millimeters in diameter, which is considered small, it had multiple “daughter sacs,” or secondary bulges that form on the aneurysm. “She (the surgeon) stopped counting at 24,” says Duff, describing the secondary bulges.

Duff had endovascular embolization surgery and spent 26 days in the neuro intensive care unit (ICU), and experienced vasospasms, a condition in which the arteries narrow as a result of blood vessel constriction and spasms, every day. Duff was in and out of consciousness and doesn’t recall much, but she says Cindy Payne, her partner of over 20 years, wasn’t sure whether she’d pull through or not.

When she was finally stable, doctors told Payne to be prepared that Duff might not recognize her. “She was very happy that I not only knew her but was able to say the promise we made many, many years ago: ‘We are going to dance together on the streets when we are 84,’” Duff says.

Duff has since had two surgeries to repeat the treatment, and after the last one, her doctor advised her to quit smoking. “Your odds of surviving as long as I have are unusual,” Duff says.


Watch the video: Princess Chelsea The Cigarette Duet hourly version (May 2022).