Tag Archives: national institutes of health

Smoking’s Effects on Genes May Play a Role in Lung Cancer Development and Survival

Smoking plays a role in lung cancer development, and now scientists have shown that smoking also affects the way genes are expressed, leading to alterations in cell division and regulation of immune response.

Notably, some of the changes in gene expression persisted in people who had quit smoking many years earlier.

These findings by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, appeared in the Feb. 20, 2008, issue of PLoS ONE.

“Smoking, we are well aware, is the leading cause of lung cancer worldwide,” said NCI Director John E. Niederhuber, M.D. “Yet, a mechanistic understanding of the effects of smoking on the cells of the lung remains incomplete. This study demonstrates an important piece of this complicated puzzle. Greater understanding of the genetic alterations that occur with smoking should provide greater insight into the development of cellular targets for treating, and possibly preventing, lung cancer.”

“We were able to look at actual lung tissue, tumor and non-tumor, taking into account the differences by gender, verifying the smoking status by measuring levels of cotinine, a metabolite of nicotine, in participants’ plasma, and confirming results in independent samples,” said Maria Teresa Landi, M.D., Ph.D., in NCI’s Division of Cancer Epidemiology and Genetics, the first author of the study report.

To investigate the effects of smoking on gene activity in lung tissue, the researchers examined the gene expression profiles — patterns of gene activity — in early-stage lung tumors and non-tumor lung tissue of smokers, former smokers, and people who had never smoked cigarettes. Gene expression was measured in 58 fresh-frozen tumor and 49 fresh-frozen non-tumor samples from 74 participants of the Environment And Genetics in Lung cancer Etiology (EAGLE) study, a large lung cancer study that was conducted in the Lombardy region of Italy.

Adenocarcinoma tumor samples were evaluated in this study because adenocarcinoma is the most common type of lung cancer, and it occurs in both smokers and people with no history of smoking. The participants were 44 to 79 years of age, and 28 were current smokers, 26 were former smokers, and 20 had never smoked. The researchers also obtained detailed medical information about the participants (for example, whether individuals had previous lung diseases or chemotherapy) and biochemically confirmed participants’ smoking status.

Using microarray techniques, which allow researchers to look at the activity of thousands of genes simultaneously, they identified 135 genes that were differently expressed in tumors of smokers vs. people who had never smoked. Among these genes, 81 showed decreased expression and 54 showed increased expression in tumor tissue.

Most of the genes showing significantly increased expression, e.g., TTK, NEK2, and PRC1, are involved in cell cycle regulation and mitosis. The cell cycle is a step-wise sequence of events in which a cell grows and ultimately divides to produce two progeny, or daughter, cells. During the cell cycle, the chromosomes of the parent cell are duplicated and then, in a step called mitosis, divided equally between the daughter cells, ensuring that each daughter cell inherits a complete set of chromosomes. The cell apparatus responsible for the proper division of chromosomes is called the mitotic spindle.

Picture of Lungs“Our results indicate that smoking causes changes in genes that control mitotic spindle formation,” said Jin Jen, Ph.D., in NCI’s Center for Cancer Research, a senior author of the study report. “Irregular division of chromosomes and chromosome instability are two common abnormalities that occur in cancer cells when the chromosomes do not separate equally between the daughter cells. Therefore, changes in the mitotic process are very relevant in the development of cancer.” Several of the identified genes have been suggested in the past as potential targets for cancer treatment.

The researchers also found similar expression of many genes among current smokers and former smokers in tumor tissue. Several of these genes, such as STOM, SSX2IP, and APLP2, remained altered in participants who had quit smoking more than 20 years before the study. Therefore, smoking seems to cause long-lasting changes in gene expression, which can contribute to lung cancer development long after cessation.

Looking at non-tumor lung tissues, the team found decreased activity for 73 genes and increased activity for 25 genes in current smokers. The genes most affected by smoking play a role in immune response-related processes, possibly as a lung defense mechanism against the acute toxic effects of smoking. However, non-tumor tissues seem to be able to recover from the effects of smoking. The researchers did not identify significant changes in the immune response-related genes in former smokers.

To gain a better understanding of the impact of smoking-related changes in gene expression on lung cancer survival, the researchers compared the overall gene expression smoking profile in lung tumor and non-tumor tissues with survival. They found that the altered expression of the cell cycle-related genes NEK2 and TTK in non-tumor tissues was associated with a three-fold increased risk of lung cancer mortality in smokers.

“Our data provide clues on how cigarette smoking affects the development of lung cancer, indicating that the very same mitotic genes known to be involved in cancer development are altered by smoking and affect survival. More studies are needed to confirm that the gene expression changes are due to smoking and affect tumor development or progression,” said Landi. “If confirmed, these genes could become important targets for preventing and treating lung cancer.”

About 90 percent of lung cancer deaths among men and almost 80 percent of lung cancer deaths among women can be attributed to smoking. In 2006, approximately 20.8 percent of U.S. adults were cigarette smokers. Cigarette smoking remains the leading preventable cause of death in the United States, causing an estimated 438,000 deaths, or about one out of every five deaths each year.

For more information on research in Dr. Landi’s group, please go to http://dceg.cancer.gov/about/staff-bios/landi-maria.

For more information about the EAGLE study, please go to http://dceg.cancer.gov/eagle.

For more information about cancer, please visit the NCI website at http://www.cancer.gov/, or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


Reference:
Landi MT, Dracheva T, Rotunno M, Figueroa, JD, Liu H, Dasgupta A, Mann FE, Fukuoka J, Hames M, Bergen AW, Murphy SE, Yang P, Pesatori AC, Consonni D, Bertazzi PA, Wacholder S, Shih JH, Caporaso NE, and Jen J. February 2008. Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival. PLoS ONE. Vol. 3, No. 2.

Corticosterone, Genetics And The Addiction Of Nicotine

Individual brain chemistry and genes could be key to understanding why some people become addicted to nicotine and why the chemical compound’s effects appear to diminish at night, University of Colorado at Boulder researchers say.

“The depth of a person’s addiction to nicotine appears to depend on his or her unique internal chemistry and genetic make-up,” said lead author Jerry Stitzel, an assistant professor in CU-Boulder’s department of integrative physiology and researcher with CU-Boulder’s Institute for Behavioral Genetics.

He and his team set out to evaluate the effects of nicotine over the course of a day by examining mice that could make and “recognize” melatonin, a powerful hormone and antioxidant, and others that could not. Scientists believe that melatonin, which is produced by darkness, tells our bodies when to sleep.

The CU researchers found that the reduced effects of nicotine at night were dependent on the mice’s genetic make-up and whether their brains and bodies were able to recognize melatonin. They also found that the daytime effects of nicotine were greatest when levels of the stress hormone corticosterone were high.

The second finding could explain why many smokers report that the first cigarette of the day is the most satisfying. Cortisol, the human equivalent of corticosterone, is at peak levels in the early morning, Stitzel said.

“The negative health consequences of smoking have become well known, and a large majority of smokers say that they would like to quit,” Stitzel said. “As such, we need to understand the interaction between smoking, genes and internal chemistry so we can target new therapies to those who have a hard time quitting.”

While the team’s research could shed light on why people smoke and how nicotine affects them, Stitzel says more research is needed to determine the role that melatonin plays in altering the effects of nicotine, and whether the correlation between higher corticosterone levels and nicotine sensitivity is a coincidence.

The CU-Boulder study was funded by the National Institute on Drug Abuse, a part of the National Institutes of Health.

CorticosteroneResearchers from Yale, Florida State, the University of Minnesota and the Baylor College of Medicine also presented findings based on research into the effects of smoking and nicotine.

Among their conclusions: Smoking may predispose adolescents to mental disorders in adolescence and adulthood; a network of neurons, or cells in the nervous system, may regulate the body’s craving response; and smoking may affect decision-making.

– University of Colorado at Boulder

*Thanks goes to Cuckoo from AS3 for submission to CF.

NIH to Fund New Research Study Regarding Exposure to Cigarette Smoke

Smoking Research Studies Exposure to Cigarette Smoke

Researchers at the University of Pennsylvania recently received a $2.3 million grant from the National Institutes of Health for a new study focusing on the chemical changes that occur when the body is exposed to cigarette smoke.

SmokePrevious research has shown that chemical changes in the body can occur after exposure to cigarette smoke and that smoking and exposure to cigarette smoke is the environmental exposure responsible for causing more deaths than any other toxins.

The chemical elements found in cigarette smoke can cause certain types of cancer and have been associated with cardiovascular, pulmonary and pancreatic diseases.

Smokers, non-smokers and even individuals who are in regular contact with secondhand smoke will be screened for the presence of distinctive lipid and DNA biological indicators or chemicals and through additional discovery potential protein indicators in their blood, urine and breath.

These indicators, also known as biomarkers or biochemicals, will be utilized to determine the susceptibility of individuals to tobacco-related lung and cardiovascular problems after exposure to cigarette smoke. The results will hopefully provide reliable data for use in subsequent studies.

“Only one in ten smokers get lung cancer, but the five-year survival rate after diagnosis is only 15 percent,” says Trevor M. Penning, PhD, Director of The Center of Excellence in Environmental Toxicology (CEET). “The question is, how can we intervene earlier to identify people most at risk. We aim to look at the interaction of genetic susceptibility to lung cancer and biomarkers of exposure to cigarette smoke. At the end of the day, if we study genetics and exposure together, we’ll hopefully have a very strong statement to say who is most at risk.”

Source: Brenda Fulmer, Claris Law
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Why Doesn’t Every Smoker Get Emphysema?

Researchers Say It Takes Genes, Viruses and Cigarettes

Physicians say that smoking is by far the biggest cause of emphysema, but why doesn’t every smoker get the disease? If you asked Michael Holtzman, M.D., that question, he might answer that for most cases of emphysema you need a mix of genes, viruses and cigarettes.

Emphysema and the associated condition of chronic bronchitis are both disorders that contribute to chronic obstructive pulmonary disease (COPD), which is the fourth leading cause of death in the United States.

Research by Holtzman and his colleagues at Washington University School of Medicine in St. Louis suggests that someone destined to suffer from COPD may start with a susceptible genetic makeup and then experience a severe viral lung infection in early childhood.

Young Woman Picture The infection could “reprogram” the cells of the lung’s air passages and sacs, and the reprogrammed cells could react badly if the same person took up cigarette smoking, leading to COPD some time down the road.

“Cigarette smoking has created a very large population of COPD patients worldwide,” he says. “At present, we can treat them with steroids to reduce inflammation, antibiotics to suppress infections, and oxygen to help their breathlessness, but the disease will still progress until it’s fatal. We need to find treatments that stop the disease progression and to do that we need a much better understanding of how COPD develops.”

Now Holtzman and his colleagues at the School of Medicine have obtained funds from National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) totaling $14.9 million to establish a Specialized Center for Clinically Oriented Research (SCCOR), an ambitious type of grant program meant to foster research that can quickly apply basic science findings to clinical problems.

Holtzman’s SCCOR program will take a comprehensive look at the molecular changes that occur as lungs become crippled by COPD, a disease that affects at least 16 million people in the United States today.

Lungs have a tree-like structure of intricately branching airways ending in tiny sacs or alveoli, which exchange gases between the blood and the air. In chronic bronchitis, airways overproduce mucus and become inflamed, obstructing airflow. In emphysema, alveoli are destroyed so they can no longer take up oxygen from the air. COPD patients can have both problems at once, and Holtzman and his colleagues are studying both issues.

Researchers will use newly developed imaging techniques, such as helium MRI, to look at the tissue of lungs removed from COPD patients undergoing lung transplants and home in on the tiny lung structures that are injured. “Then, if we find that a particular gene is overactive at a site where the disease is particularly severe, we’ll analyze the normal and abnormal function of that specific gene,” Holtzman says.

Holtzman notes that so far no other researchers have done this because it takes a combination of new imaging techniques, advanced gene analysis technologies and a highly active lung transplant program, all of which are on hand at the School of Medicine.

COPD Facts

  • COPD is the 4th leading cause of death in the US and the 2nd leading cause of disability
  • COPD kills more than 120,000 Americans each year. That’s one death every 4 minutes
  • More than 12 million people are diagnosed with COPD
  • An additional 12 million likely have COPD and don’t even know it

For more information go to learnaboutcopd.org.

Source: Consumer Affairs Original Publication Date: January 22, 2007