Although cigarette use has long been linked to lung cancer, scientists have not understood how the earliest changes in lung cells developed. In a study published in Cancer Cell, researchers showed how cigarette smoke sensitized airway cells to genetic mutations that are known to cause lung cancers.

Epigenetic processes are essentially switches that control a gene’s potentially heritable levels of protein production but without involving changes to the underlying structure of a gene’s DNA. Genetic and epigenetic changes also occur when normal cells undergo chronic stress, such as the repeated irritation and inflammation caused by decades of exposure to cigarette smoke.

The study was conducted on lab-grown human bronchial cells, which line the airways of the lungs. The researchers exposed the cells daily to a liquid form of cigarette smoke that was comparable to one to two packs of cigarettes daily. They recorded the molecular and genetic changes over 10–15 months, which was comparable to 20–30 years of smoking.

After three months of smoke exposure, the cells had increased EZH2, an enzyme that decreases gene expression, and DNMT1, a protein that maintains tumor suppressor genes that normally stop cancer growth. After 10–15 months, scientists found decreased expression of hundreds of key tumor suppressor genes and a fivefold increase in KRAS oncogene signaling, which is known to be mutated in smoking-related lung cancers.

They also tested the timing of the epigenetic changes by inserting KRAS mutations at 6 and 15 months, but cancer only developed in the cells exposed to smoke for 15 months, where methylation was fully established.

The researchers said that the findings may suggest future research into the use of demethylating drugs for people at a high risk for lung cancer. They also cautioned that their study used traditional cigarette smoke and the results cannot be applied to e-cigarettes or other forms of tobacco.

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