Genetic Changes in Airways May Predict Which Smokers Get Lung Cancer

Genetic Changes in Airways May Predict Which Smokers Get Lung Cancer

Apr 15, 2010 3:45 PM

SALT LAKE CITY – Scientists from the University of Utah are part of a national team of researchers that has identified a gene pathway that is activated in the airways of people with lung cancer and smokers with precancerous lesions. According to their study published April 7 in the journal Science Translational Medicine, treatment with an inexpensive and widely available natural supplement may reverse this pathway activation and help to prevent lung cancer in high-risk smokers.
Cigarette smoke is the leading cause of lung cancer in the United States, accounting for approximately 90 percent of all cases. Unfortunately, there is currently no reliable test for determining which smokers are at highest risk for developing lung cancer and it can be difficult to detect early-stage tumors.
“We have limited knowledge of the gene pathways that are altered early in the development of lung cancer,” says Andrea Bild, Ph.D., assistant professor of pharmacology and toxicology at the University of Utah College of Pharmacy and a contributor to the study. “However, we do know that cigarette smoke causes injury to the entire respiratory tract and not just the lung. So, we can use tissue from the airways to study early smoking-induced damage.”
Bild and her colleagues studied normal bronchial airway epithelium from smokers both with and without lung cancer and found that activity of a gene pathway called phosphatidylinositol 3-kinase (PI3K) is significantly increased in the airway cells of smokers with lung cancer. This airway PI3K activation was specifically associated with lung cancer, rather than cumulative smoke exposure, smoking status or presence of other lung diseases.

“Although lung cancer develops deep in the lungs, PI3K activation is present even in normal airway cells of smokers with lung cancer,” explains Bild. “What this means is that we may be able to identify smokers who are at risk for, or already have, lung cancer by using a brush to collect cells from their windpipes rather than by performing more complicated or invasive lung tests.”

When they studied actual lung cancer tissue, the scientists found that PI3K pathway activity was increased in tumor tissue compared to the normal tissue surrounding it. The researchers also discovered that PI3K pathway activation is already present in smokers with mild to moderate airway dysplasia, cellular abnormalities that often are considered to be precancerous. These findings suggest that deregulation of the PI3K pathway is an early event in the development of lung cancer and it persists as cells undergo malignant transformation.
To determine whether reducing PI3K pathway activity could prevent lung cancer, Bild and her colleagues looked at the airway cells of smokers with dysplasia who were treated with myo-inositol, a natural oral supplement that is thought to inhibit PI3K. Myo-inositol is also found in fruits, beans, grains, and nuts. The researchers found that, in smokers whose dysplasia regressed after treatment with myo-inositol, PI3K also became less active.
“Our studies suggest that myo-inositol inhibits PI3K activity, leading to regression of airway dysplasia and potential prevention of lung cancer,” says Bild. “However, these preventive effects still need to be confirmed in larger trials.”

Lung cancer is most often diagnosed at a late stage when treatment options are limited and frequently ineffective. The groundbreaking findings of this study may improve prevention and early diagnosis of lung cancer, and this deeper insight into the gene pathways involved in the development of lung cancer may also lead to improved therapies.

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