New research results reinforce the benefits of quitting smoking.
Not only does it stop further damage to the lungs, it appears that it also allows new, healthy cells to actively replenish the lining of the airways. This shift in the proportion of healthy cells to damaged cells could reduce the risk for lung cancer, say researchers.
The findings were published online January 29 in Nature.
The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.
The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of "driver" mutations, which increase the potential of cells to become cancerous.
However, they also found that in ex-smokers but not in current smokers up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.
"People who have smoked heavily for 30, 40 or more years often say to me that it's too late to stop smoking the damage is already done," commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
"What is so exciting about our study is that it shows that it's never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco," he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.
This study has "broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung," writes Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writing in an accompanying comment.
"It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation," he added.
Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, United Kingdom, added that the study has "an important public health message.
"Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices," he said.
"Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics," James added.
In an interview with Medscape Medical News, Campbell said that the team would next like to try "to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly."
He continued: "If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.
"Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways."
Campbell concluded that they are "a long way away yet, but the toolkit exists for getting there."
In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.
However, this does not explain why individuals who stop smoking in middle age or earlier "avoid most of the risk of tobacco-associated lung cancer."
They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they mused.
To investigate further, the team set out to examine the "landscape" of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.
All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.
The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
The results showed there was "considerable heterogeneity" in mutational burden both between patients and in individual patients.
Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10-8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2330 per cell in ex-smokers and 5300 per cell in current smokers.
The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, "even within the same individual."
They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2350 per cell in ex-smokers and 2100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P < 10-16 for within-subject heterogeneity).
Between individuals, the mean substitution burden was 1200 per cell in ex-smokers, 1260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10-8 for heterogeneity).
Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells, vs 4%14% of cells from adult never-smokers and none of the cells from children.
It was calculated that current smokers had a 2.1-fold increase in the number driver mutations per cell in comparison with never-smokers (P = .04).
In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5000 extra somatic mutations per cell (P = .0003).
However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.
Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.
Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.
"Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation," the team writes.
They argue that the presence of longer telomeres suggests they are "recent descendants of quiescent stem cells," which have been found in mice but "remain elusive" in human lungs.
"The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens," they suggest.
"Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface," they add.
However, in his commentary, Pfeifer highlights that a "potential caveat" of the study is the small number of individuals (n = 16) from whom cells were taken.
In addition, Pfiefer notes that the "lack of knowledge" about the suggested "long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers' cells with few mutations."
The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Campbell and Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
Nature. Published online January 29, 2020. Abstract, Comment
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Stopping Smoking Allows Healthy Lung Cells to Proliferate - Medscape
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