University Of Pittsburgh Scientists Find Biological Clue To Why Ex-Smokers Develop Lung Cancer Many Years After Quitting

August 21, 1997

PITTSBURGH, Aug. 5 -- Smoking for at least 25 years appears to trigger a biological switch that drives the growth of lung cells. Once set in motion, this process could lead to cancer, according to researchers at the University of Pittsburgh Cancer Institute (UPCI) in a report published in the August issue of the Journal of Respiratory and Critical Care Medicine.

"We believe that this switch is a smoking-related indicator of lung cancer risk because we see it activated in most individuals with a long history of smoking, regardless of whether they already have developed cancer," said Jill Siegfried, Ph.D., associate professor of pharmacology at the University of Pittsburgh School of Medicine and director of basic science at the University of Pittsburgh Cancer Institute's Lung Cancer Center.

"Once this switch is turned on, it appears to be permanent, which may explain in part why long-term ex-smokers who have not had a cigarette in over 25 years are still at high risk for getting lung cancer. Knowing when this switch appears in someone's lung could help clinicians administer chemopreventive drugs to avert the final transformation of these cells into cancer. Better still, if we can turn off this switch, we might significantly reduce the odds that an ex-smoker will ever get lung cancer," she added.

The "switch" is gastrin-releasing peptide (GRP) receptor, a protein that appears on the surface of lung cells in people with lengthy smoking histories (a pack or more a day for at least 25 years). When present, GRP receptors capture nearby circulating hormones (bombesin-like peptides, or BLPs), which are normally important for maturation of fetal lungs and which spur lung cells to divide in the mature organ. After the GRP receptor appears in an ex-smoker's lung, new clusters of lung cells form. These new cells, in turn, may continue to express GRP receptors which capture more BLPs in a self-perpetuating cycle leading to the unrestrained growth of lung tissue.

In their study, the investigators looked at cells lining the lungs of 37 subjects, some who were nonsmokers, some who had smoked less than 25 years and others who had smoked 25 years or longer. Only 14.7 percent of those who smoked less than 25 years expressed the GRP receptor, whereas 77 percent of those who smoked more than 25 years expressed the GRP receptor, even if they had stopped smoking some time ago. "This shows that the duration of smoking, not just whether someone smoked, is critical to expressing the GRP receptor," said Dr. Siegfried. The researchers also found that lung cells taken from patients who had chronic obstructive lung disease had a greater tendency to respond to BLPs; in other words, they grew considerably more than lung cells from individuals without this disorder in the presence of the same level of BLPs. Chronic obstructive lung disease is usually caused by long-term smoking, and it increases the risk for lung cancer.

"This finding also suggests that the GRP receptor switch in patients with chronic obstructive lung disease is more sensitive than in people without this lung disorder."

"Our study is an important first step. We are currently conducting a large-scale study of smokers and nonsmokers to confirm these findings and expand our understanding of the steps between smoking and the development of lung cancer, which is a very complex process," added Dr. Siegfried.

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For additional information about the University of Pittsburgh Medical Center or the University of Pittsburgh Cancer Institute, please access the website http://www.upmc.edu. Pitt's website for the department of pharmacology is http://www.pitt.edu/~pharmwww/.
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University of Pittsburgh Medical Center

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